Blood Safety Transcripts

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

Eighteenth Meeting

"Prioritizing Decisions in Transfusion Medicine: Transfusion Transmissible Diseases."

8:33 a.m.
Thursday, January 23, 2003

Hyatt Regency Hotel on Capitol Hill
400 New Jersey Avenue, N.W.
Washington, D.C. 20001

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

Committee Members

• Mark Brecher, M.D., Chairman
• Larry Allen
• Celso Bianco, M.D.
• Richard Davey, M.D.
• Ronald Gilcher, M.D.
• Edward D. Gomperts, M.D.
• Paul F. Haas, Ph.D.
• W. Keith Hoots, M.D.
• Dana Kuhn, Ph.D.
• Jeanne Linden, M.D.
• Lola Lopes, Ph.D.
• Gargi Pahuja
• John Penner, M.D.
• Mark Skinner, J.D.
• John Walsh

Non-Voting Government Representatives

• Mary E. Chamberland, M.D.
• Jay Epstein, M.D.
• Colonel G. Michael Fitzpatrick

Consultants to the Committee

• Christopher Healey, J.D.
• Captain Lawrence McMurtry

C O N T E N T S

AGENDA ITEM PAGE

• Call to Order, Introduction of Members, Conflict of Interest 4
• Review of Original Institute of Medicine report- Paul McCurdy 18
• Introduction and review of prior ACBSA recommendations - Mark Brecher, Chair 28
• Break
• Ethical Considerations of Medical Deciions - Jonathan Moreno 87
• Remarks Regarding the Committee Charter - Eve Slater 125
• Lunch
• Putting Risk in Perspective
• Overview of Viral Risks and Critical Issues of NAT screening - Michael Busch 135
• CDC Update on West Nile Virus - Mary Chamberland 184
• Procleix NAT Testing Platform - Neil Gunn 218
• Roche Platform NAT Testing - Paul Chapman 247
• NAT Testing for Source Plasma - Gerold Zerlath 259
• Prioritizing Risk in Transfusion Medicine - James AuBuchon 276
• Committee Discussion 310
• Adjournment 324

P R O C E E D I N G S

DR. BRECHER: Everyone please take their seats. We would like to begin.

I would like to welcome everyone to the 18th Meeting of the Advisory Committee on Blood Safety and Availability. I'm going to work hard to keep this on time. There was an agenda that's available in members' packages, and we're going to try to stick to that, although we're going to do a couple flip-flops of speakers.

We're going to have a roll call and a conflict of interest which is going to be reviewed by Mac McMurtry.

CAPTAIN McMURTRY: Let's do the roll call first. Larry Allen?

[No response.]

CAPTAIN McMURTRY: Celso Bianco?

DR. BIANCO: Here.

CAPTAIN McMURTRY: Mark Brecher's here. Rajen Dalal called last night, said he's not going to be able to come.

Rick Davey?

DR. DAVEY: Here.

CAPTAIN McMURTRY: Ron Gilcher?

DR. GILCHER: Here.

CAPTAIN McMURTRY: Ed Gomperts?

DR. GOMPERTS: Here.

CAPTAIN McMURTRY: Paul Haas?

DR. HAAS: Here.

CAPTAIN McMURTRY: Chris Healey?

MR. HEALEY: Here.

CAPTAIN McMURTRY: Keith Hoots?

DR. HOOTS: Here.

CAPTAIN McMURTRY: Harvey Klein is not here yet.

Dana Kuhn?

DR. KUHN: Here.

CAPTAIN McMURTRY: Jean Linden?

DR. LINDEN: Here.

CAPTAIN McMURTRY: Karen Lipton is with the AABB Board of Directors.

Lola Lopes?

DR. LOPES: Here.

CAPTAIN McMURTRY: Gargi Pahuja?

MS. PAHUJA: Here.

CAPTAIN McMURTRY: John Penner?

DR. PENNER: Here.

CAPTAIN McMURTRY: Mark Skinner?

MR. SKINNER: Here.

CAPTAIN McMURTRY: John Walsh?

MR. WALSH: Here.

CAPTAIN McMURTRY: And Dr. Winklestein called, and he's not going to make it today.

Next is the new and approved ethics statement. I'd like for all of you to settle back and get comfortable, take a deep breath.

Ethics rules for Committee members appointed to Federal Advisory Committees as special government employees. The Ethics Division of the Office of General Counsel has asked that I explain the rules that apply to you as special government employees or SGEs. If you have any questions, let me know. I'll seek assistance from the attorneys in the Office of General Counsel. All matters I'll be discussing are explained in more detail in a handout that I will provide to you, but haven't yet.

Pursuant to several sections of the Public Health Service Act, as amended by the U.S. Code and various provisions of the Federal Food Drug and Cosmetic Act, the Secretary of the United States Department of Health and Human Services has authority to carry out research in health fields including diseases involving blood and blood products, and for issuing and enforcing regulations concerning the collection, preparation and distribution of blood and blood products. The Advisory Committee for Blood Safety and Availability will advise, assist, consult with, and make recommendation to the Secretary and the Assistant Secretary of Health regarding these broad responsibilities.

The Chair and other members are special government employees, appointed to perform duties on an intermittent basis not to exceed 130 days during any 365-day period. I have the U.S. Code reference for this authority if anybody would like to see it.

All Committee members appointed as SGEs are required under the Ethics in Government Act, amended by the Ethics Reform Act of 1989 to file a financial disclosure report when first appointed and annually thereafter. The information reported is used to determine the matters for which a Committee member must be disqualified under the Criminal Conflict of Interest Statutes.

Let me discuss the Criminal Ethics Statutes here for a second. SGEs are subject to a number of criminal ethics statutes. Violation of the bribery provision imposes substantial fines and/or imprisonment. A violation of any of the other U.S. Code provisions is punishable as a Class A misdemeanor, and subject to fine and imprisonment. Willful violation of the Code elevates the commission to a felony, and the Attorney General may opt for several penalties.

In a civil action the government need only prove the violation by a preponderance of the evidence rather than by the criminal standard requiring proof beyond a reasonable doubt.

I need to describe these various statutes. First is a bribery statute which prohibits Federal employees, including SGEs, from seeking, accepting or agreeing to receive anything of value in return for being influenced in the performance of an official act. There is the example of a person receiving a brown paper bag of money in exchange for recommending to the Secretary.

There is the Anti-Representation Statute, which prohibits an SGE from receiving compensation for representational services rendered by the employee or another person before HHS or another Federal agency or other specified entity such as a court or committee in any particular matter involving a specific person (1) in which the SGE has participated personally and substantially as a government employee, or (2) which is pending in a government agency in which the SGE is serving if the SGE has served more than 60 days during the immediately preceding 365 days.

The Post Employment Statute imposes a lifetime ban on a former SGE from representing another person or entity to HHS or other Federal agency or other specified entity such as a court in any particular matter involving a specific party in which the former SGE participated personally and substantially while serving in the government.

The Financial Conflict of Interest Statute, the main Conflict of Interest Statute, prohibits an SGE from participating personally and substantially in any particular matter that could affect the financial interest of the SGE, the SGE's spouse, minor child, general partner, and organization in which the SGE serves as an officer, director, trustee, general partner or employee, or an organization with which the SGE is negotiating or with which the SGE has an arrangement for prospective employment. Specifically, you as an SGE cannot work on matters affecting your financial interest or those of your spouse, minor children or organization with which you are affiliated.

An example would be owning stock in pharmaceutical company X which produces a test for viral contamination. You cannot participate in decisions or discussions to partner with company X to promote that test.

You must also disqualify from matters affecting your financial interest as a class. For example, the same scenario, you own stock in a pharmaceutical company that produces a test for viral contamination. You cannot participate in decisions regarding testing for viral contamination. However, broad matters of national policy that don't focus on a specific industry are not a problem.

Under regulatory waiver issued by the Office of General Ethics, you may participate in matters affecting your employees a matter of a class, but not in a manner that will affect the employee specifically. For example, you may recommend a grant program be established even though the university for which you work will be eligible, but you may not participate in consideration of a specific grant application submitted by your university.

Additionally, while this exemption will allow you to participate in any matter of general applicability that would affect the financial interest of a specific, we'll say Harvard Medical School and/or Harvard University as a member of a discreet and identifiable class of similarly situated medical schools or universities. The exemption will not protect you from violation of the criminal statute if the matter will have a special or distinct effect on Harvard Medical School or Harvard University. This means that you can participate in generally applicable matters such as legislation, regulation or policy that affects medical schools or university as a class. The same rule applies with respect to other types of employers, so that if you work for a pharmaceutical company, you can participate in matters affecting your employer as a member of a class. However, if you have any other interest besides employment, such as stockholding, you must disqualify from all matters, even if it only affects that employer as part of an industry sector.

On the other hand, another regulatory exemption, if you're under another regulatory exemption, if your financial interest is in publicly traded securities valued at less than $25,000, you can work on matters affecting as part of industry sector. But again, you have to avoid matters that will have a specific effect on that company.

You may receive compensation for speaking engagements, or writing undertaken in a personal capacity. However, you may not receive compensation for speaking or writing that was undertaken as part of your official duties as a member of the committee that draws on nonpublic information to which you have access as a member of the committee, nor if the invitation was extended primarily because of your membership on the committee. You may receive gifts where circumstances make it clear that the gift was not offered as a result of your membership on the committee.

Generally you should not use your position to imply that the Committee or the government endorses your private activities. You should not disclose nonpublic information to which you have access. You may state your personal opinions, but should not imply that you were speaking for the Committee unless you are actually authorized to do so.

There is an issue regarding fund raising. You may do personal, charitable fund raising, but you may not personally solicit funds from someone who has business before the Committee. Under the Constitution. While you serve as an SGE, you may not have an employment relationship with a foreign government. That is, you can't be reimbursed by a foreign government. This may include foreign public universities and government owned companies, depending on the degree of control the foreign government exercises. Under the Foreign Gifts and Declarations Act, you generally may not accept gifts from a foreign government unless the worth is under $260.

In your official capacity or as a group, Committee members are prohibited from engaging in any activity which directly or indirectly encourages or directs any person or organization to lobby one or more members of Congress. When authorized, Committee members may appear before any individual or group for the purpose of informing or education of the public about a particular policy or legislative proposal. Committee members may also communicate to members of Congress at the request of any representative or senator. Communications to members of Congress initiated by Committee members in their official capacity as members of the Committee, should be coordinated through the Office of the Assistant Secretary for Legislation.

As private citizens Committee members may express their personal views, but not the view of the Committee as a whole or the opinions of HHS to anyone. In so doing, Committee members may state their affiliation with the Committee, may factually state the Committee's official position on the matter to the extent that nonpublic information is not used, but may not take new positions and represent those views as the Committee's position on the matter. Moreover, in expressing their private views, as will all other personal nongovernment activities, Committee members are not permitted to us government computers, copiers, telephones, letterhead, staff resources or other appropriated funds. All personal activities must occur off-duty time.

And finally, the Hatch Act prescribes that restrictions on certain political activities of Federal employees. Unlike the criminal statutes and most other ethics rules, which are fully applicable to an SGE throughout your entire term of appointment, the Hatch Act restrictions apply only during the period of any day in which you are actually performing government duties. For example, if an SGE attends an Advisory Committee meeting from 8 to 1, and at 3 o'clock the--if you attend the meeting during the day, the SGE may attend a political fund raiser or even solicit political contributions after they leave the Committee meeting that day.

That's it. Thank you.

DR. BRECHER: That was enough, Mac.

[Laughter.]

CAPTAIN McMURTRY: Well, I tried to get us off to a flying start.

DR. BRECHER: All right, thanks.

The purpose of this meeting is to review prioritizing decisions in transfusion medicine, and we're going to use transfusion-transmitted diseases as a take-up point for our discussions, but before we get into the meat of that, most of this morning is going to be going over some background material for the Committee, why we have this Committee, where we've been before, and what has the Committee accomplished.

So to start that off, and for those of you who have the agenda, I flipped the first two speakers. And so we're going to review the original Institute of Medicine report which led to the creation of this Committee, and Paul McCurdy is going to do that. And there is a copy of a transfusion article in the Committee members' packages that summarize the IOM report.

Paul?

DR. McCURDY: I gather they have the Executive Summary of the report; is that what you referred to, Mark?

DR. BRECHER: Yes, that's essentially what they have.

DR. McCURDY: I think Mac forgot one item, and that is, pay attention under penalty of law.

[Laughter.]

DR. McCURDY: Mr. Chairman, Committee members and guests, I'd like to thank the organizers for inviting me to present today on some of the activities surrounding the genesis of this Committee. When you get old enough, you are considered a historian, I guess, and maybe you remember these things and can talk about them.

This report that's entitled on the screen here, "HIV and the Blood Supply: An Analysis of Crisis Decision Making," was a major factor in the genesis of this Committee. As you will see, there were other factors, most notably activities of the Committee on Oversight of the Congress of the United States that played a major role.

In 1993 Senators Kennedy and Graham and Congressman Porter Gross asked Dr. Shalala, who was then the Secretary of DHHS, to review the government's role in the matters that led to the infection of patients with hemophilia and blood transfusion, following blood transfusion, their infection with HIV in the early '80s. Dr. Shalala responded by commissioning the IOM to do this study.

The report was released in July 13th, 1995. I well remember a late afternoon briefing for some members of the administration, and I was privileged to be one of the representatives of NIH that attended that briefing one or two days before the release of this report. It was highly critical of PHS leadership in failing to override long-standing blood bank conservatism. There was discussion using core antibody for hepatitis B as a surrogate test for HIV. There were very limited data in 1983 to lead to that, but in retrospect--the retrospectoscope is an excellent instrument--in retrospect it would have been a good test.

Anyhow, there was concern expressed that changes in recruiting donors, in asking questions of donors, would lead to shortages and patients would die for lack of blood. There was also discussion that changes would be too costly and who would pay.

I sat on the sidelines during this--some of these discussions, and I think that many of the people involved did remarkably well with what they had to work with. But nevertheless, they were criticized because of the alleged limited public health response.

Nevertheless, Dr. Shalala, when she received the report, despite its many faults, had a public relations press release that accepted the report and its recommendations except for a compensation plan which was mentioned in the report and has essentially disappeared.

One of the things that happened was a task force was put together to implement the recommendations of the Committee. This rapidly became the Internal Blood Safety Committee, which was not recommended by the IOM report, but it was in keeping with its goals. That comprised of the directors of CDC, NIH and the FDA Commissioner, and they often brought people to the meeting with them when these--when various matters were discussed.

The acceptance of the report was reiterated at a meeting of the Subcommittee on Government Reform, who held a hearing on October 12th, 1995. This is one of the few committees in Congress that has individuals testifying under oath, and hence what they say carries perhaps a little more weight, and they can be held responsible for it. It's a little different than many of the other committees of the Congress.

The first recommendation was that the Secretary appoint a Blood Safety Director at a very high level, and Dr. Phillip Lee was appointed the first Blood Safety Director. At that time he was the Assistant Secretary for Health, and most commonly, that office has been filled by the Assistant Secretary for Health. And he chaired the Internal Blood Safety Committee.

The Internal Blood Safety Committee began by meeting fairly frequently, but now meets essentially on call when an item seems to be of sufficient import to take it to that level.

The second recommendation which is most pertinent perhaps to this committee, was a recommendation for what they call the Blood Safety Council, but this now has metamorphosed to the Advisory Committee on Blood Safety and Availability. It was meant to report to the Secretary through the Blood Safety Director, and advise on global public health service issues, and differed in that fashion from BPAC.

In you handout you'll find that the Blood Safety Council--and this is a quote--was "to assess current and potential future threats to the blood supply; to propose strategies for overcoming these threats"--this is the recommendation now of the IOM--"to evaluate the responses of PHS to these proposals; and to monitor the implementation of these strategies."

The Council should alert scientists. The Council should alert scientists about opportunities and needs for research to maximize the safety of the blood supply, and it should take the lead to ensure the education of public health officials, clinicians and the public about the nature of threats to the blood supply and the public health strategies dealing with these threats.

Now, the congressional subcommittee that I mentioned previously, the Subcommittee on Human Resources of the Government Oversight and Reform Committee was chaired by Congressman Shays, and there was a great deal of interaction between his committee and DHHS staff. The congressional committee actually undertook a long-term, four or five-year period of continued careful oversight of what the Federal Government and the PHS was doing in the way of blood safety.

The charter of the Committee, which is how it operated for the first, I guess, six or eight years of its activity, the charter was molded with the help of this Committee and the high-level echelons in DHHS. The initial charter was to advise the Secretary, via the Blood Safety Director, on the implications of economic factors on blood safety and availability, define public health factors that have an effect on safety and availability, and also advise on broad public health, ethical and legal issues related to blood safety.

This is a very broad charter. I think the Committee has done much of this, but I don't know that it's done it all. The most important thing is that it is advisory in that the government can take its recommendations and do or not do what they think is appropriate.

There was a lot of discussion about this Blood Safety Committee. There was a considerable delay, as is often the case in government I getting it off the ground, but there was one meeting where Phil Lee set a deadline for the first meeting, which was not made--we came close--asked that NIH run the meeting, that the FDA handle appointing the members of the Committee and CDC to pay for it. That as a rather three-headed animal that was a little hard to manage. With the efforts of a number of people, including my secretary at the time at NIH, the meeting came off. The first agenda item, which was near and dear to the heart of the congressional committee was hepatitis look-back. There were several other meetings subsequently that dealt with that, and there was another item, CJD and variant CJD as a potential threat to the blood supply, was given as an informational item to the Committee.

Now, there were several simultaneous things that went on about that time. They were not very--from my perspective--not very important, didn't have a great impact on what was going on, and did not ultimately, as far as I know, have much to do with this Committee. But it is of some interest that there was a forum on blood safety and availability convened by the IOM and supported by public and private sector organizations. It was mainly for discussion in a nonthreatening environment. It could not give advice. The FDA was one of the supporters of this group, and it had to be chartered as an advisory committee if it was going to advise.

It put forth three books over 21 months, and I think many parts of those book published in the middle '90s are still pertinent. This is a list of the organizations that supported this forum which lasted about a year and a half, and examples of subjects of blood bank regulation, blood banking and regulations, innovations and alternatives and regulation, and congressional oversight. There wa a book that deal with blood donors and the supply, spoke about enhancing collections, and of great interest to me at the time, perishable logistics. A member of a supermarket managerial staff talked about how they managed seafood in their supermarket chain around the country, and some of this is, I think, quite pertinent to the management of blood. There was also a booklet on blood and blood product safety and risk, and as I said, some of these are worth looking at.

I thank you.

DR. BRECHER: Jay? Committee members will you please identify yourselves for the transcript?

DR. EPSTEIN: Sure. Jay Epstein, FDA.

Thank you for the very nice summary, Paul, and it brings back memories to me too. One memory though that I have is that there was a lot of overlap between recommendation two, about establishing a blood safety council, and recommendation 13, about convening a standard expert panel, and my recollection, faulty as it may be, is that what happened is that the Blood Safety Committee looked at those two recommendations, tried to sort out which of the functions belonged within government and which were more properly advisory and oriented toward public process, and it's on that basis that the respective roles and functions of the blood safety committee within government and this advisory committee were crafted.

So it's not purely that the recommendations under number two are the basis for the charter of this advisory committee. It was a little bit of mix and match.

DR. McCURDY: You're absolutely right, and there was a lot of discussion with the congressional subcommittee staff that tried to formulate how the committee should, this committee should operate. I appreciate your better memory than I, in some of the areas at least.

DR. BRECHER: Other questions or comments?

[No response.]

DR. BRECHER: If not, thank you, Paul. That was very helpful.

We're going to move on to a review of the Committee recommendations. And I had asked Mac to pull together a grid of all the prior recommendations and the current status of what has happened with those recommendations through the years, and they are in the Committee members' package. Now, this is a rough draft, and we welcome input from members and others who know the impact of these recommendations that may have gone beyond the government, and so--I know there are a few typos in here as well. We'll capture those.

This is a long document, and we only scheduled an hour and it's going to be somewhat dry, but we're going to try to very quickly run through this document.

So as Paul originally outlined, that the Committee initially began its work on hepatitis C in 1997, and the initial recommendations were that the Committee recommended that a program to educate providers in medical care regarding the importance of identification of persons at risk of HCV, including those who received blood or blood products prior to '92, and appropriate measures for prevention, counseling, diagnosis and treatment. Two, that there would be an aggressive and sensitive public education campaign to notify test recipients prior to '92, and that there be a targeted look-back program triggered by donors that were detected as HCV, and there were three stipulations that went with that.

In terms of the action, the FDA issued its guidance supplemental testing notification of consignees of donor test results for antibody to hepatitis C for March 20th of, I believe it was '98. It was withdrawn on September 8th, following further Committee recommendations, and a new guidance was issued on June 17th, 1999.

Anybody have anything to add from that committee recommendations?

[No response.]

DR. BRECHER: If not, the next meeting was January 30th, 1998. At that time the Committee addressed emerging transmissible spongiform encephalopathies. The report made special reference--I'm sorry--the Committee recommended the Public Health Service coordinate an effort, develop a report within six months that would include references to food borne transmission, particularly through consumption of central nervous system tissues, iatrogenic transmission and transmission through blood components and plasma derivatives. A BSE action plan was developed and adopted by the Department in 2001.

The Committee further recommended the Public Health Service, professional groups and patient advocates emphasize the importance of post mortem exam to the protection of the public health. They supported the training physicians to recognize new pathological patterns or emerging disease in autopsy tissues, and it is now common practice to screen suspected deaths by autopsy for variant CJD. The Committee recommended nationwide standardization of procedures for screening donors at risk for transmissible spongiform encephalopathies, and the FDA developed guidelines for screening donors at risk for TSEs.

The Committee recommended the NIH specify its need for research and infrastructure support necessary to promote research on the TSEs with particular reference to animal testing that can discriminate among these conditions within each species. And this was done. And I think this is, as an overview, one of the successes of this Committee, is we've identified areas that needed further research, and largely that has happened.

The Committee recommended that during the next year the FDA worked with the industry and consumer groups to relax current Jakob Creutzfeldt disease guidelines on quarantine and withdrawal of blood products to the extent necessary to relieve shortages. This particular recommendation was rejected.

MR. HEALEY: Mr. Chairman, just a point of clarification. Is the purpose of this exercise to just reach consensus among the Committee members about the status of the action?

DR. BRECHER: Right. I'd like to make this as accurate a document as possible, and then with the Committee's agreement we would then post it on the Web as part of the Committee's site to basically illustrate what the Committee has done. This is actually a charge from an earlier Committee didn't ever seem to happen.

MR. HEALEY: So we should be reviewing this with an eye toward whether we agree with the current status, and provide you any feedback whether we think it's accurate or not.

DR. BRECHER: That's correct.

Jay?

DR. EPSTEIN: If that's the task, Mark, I think we're not in a position to vote at this meeting, that we have to take this back and look very carefully, because there are addenda and corrections that I see. For example, the matter most recently stated, it's true that we have continued to recommend withdraw of components. However, we did adopt a recommendation to discontinue the withdrawal of plasma derivatives in the case that at-risk donor was found to have contributed to the pool for fractionation. So, you know, there are some subtle, you know, clarifications that are needed, and on a cursory reading I think that's true throughout the document.

DR. BRECHER: I think that's a good point. So what I propose we do is we just briefly roll through what we have here with the caveat that we know there are going to be a lot of changes and you have to take it back. If you could funnel all those changes to Mac, and then we'll put it together, and then we will redistribute it by e-mail to the Committee members for their blessing, once we have put it all together, with a short-range goal that maybe within a month we could have all the comments back, a month after this meeting.

April 28th, 1998, recommendations for the short term. The FDA, the International Plasma Producers Industry Association, individual manufacturers and distributors of plasma derivatives and recombinant analogs, should on a monthly basis collect and disseminate standard information on production, distribution and demand for intravenous immunoglobulin, clotting factors, and alpha1-antitrypsin. And the PPTA since 1998 has been distributing this information.

Two. The Department of Health and Human Services, should explore in collaboration with the industry, health care providers and appropriate consumer groups, methods to optimize and standardize allocation of available products in an equitable manner, including management of emergency supplies and programs, and distribute the products directly from manufacturers to registered consumers. Emergency allocations of IVIG and direct distribution of alpha1-antitrypsin programs were established through direct collaboration between consumer groups and the industry.

Three. Industry should discuss triage for specific plasma derivatives, specific patient groups with the FDA, and the Federal Trade Commission Healthcare Providers and appropriate consumer groups, to promote accountability to the public. Most programs were set up at the local level. The FDA did issue a "Dear Doctor" letter on the issue, and articles appeared in professional journals addressing this subject. It was further recommended that the industry should explore with the FDA the possibility of importing additional supplies of intravenous and intramuscular immunoglobulin. Discussions continue, and the FDA did hold a workshop on clinical comparability in October of 2000.

Five. The industry should explore with the FDA strategies for reallocating process plasma materials from one manufacturer to another, and this has occurred.

The industry should explore with the FDA labeling and disclosure strategies in which to increase product availability without compromising public safety. The FDA has addressed this issue, and pretty much remedied the situation.

Seven. The industry and government should explore the impact of a temporary decrease I exportation of derivatives while they are in short supply in the U.S. This one was received by the Department, but I believe it was basically no action.

And the long-term recommendations were that every effort should be made to make recombinant clotting factors available to all who would benefit from them, and all barriers to conversion from human to recombinant clotting factors should be removed, and this has largely been accomplished.

MR. HEALEY: Mark, would this be an appropriate time to comment on that?

DR. BRECHER: It's a good time, Chris.

MR. HEALEY: I mean I can tell you it's our impression, and perhaps those in the hemophilia community can speak better to this, but I think the impression is that this hasn't been adequately accomplished and that indeed there's some more work to be done.

MR. SKINNER: Mr. Chairman, it would be my intent--and I'll mention it now and you can decide the appropriate point in the meeting to bring it up, but I concur with what Chris has said. The National Hemophilia Foundation and others in the bleeding disorders community have been greatly concerned recently about the backsliding, particularly since the shortages of the last couple years in terms of recombinant clotting factor availability, and in fact, we're now seeing that some of the states, in light of their budget crunches are actually going backwards and beginning to try to transition the population back to plasma-based therapies from recombinant therapies, and restricting choices in treatments.

And what I would like to propose is that Committee adopt yet another recommendation reaffirming its position and putting it in context of some antiquated Medicare guidelines which the states are using to justify this, which speak to things such as heat-treated and non-heat-treated factor, which is not even current nomenclature. And so we've been word crafting a resolution that whenever it's appropriate we'll bring forward and ask the Committee to look at it again, hopefully with the intent of adopting at this meeting so it can be useful I this state legislative cycle.

DR. BRECHER: I think we can do that, and when we get to making our resolutions for that, that will be one of those that we will discuss.

Two. The NIH was asked to convene a consensus conference on the use of recombinant clotting factors. This was referred back to the Committee, which considered the issue again in its August '98 meeting, which we'll come to in just a minute.

Three. The industry should explore strategies for development of reserves of plasma derivatives and their allocation during shortages, and this was accomplished.

Four. The NIH should immediately evaluate alternative dosing schedules and alternative delivery systems for alpha1-antitrypsin therapy, including prophylaxis and strategies for treatment during acute exacerbation, and accelerate development of gene-based product and gene-directed therapies for alpha1-antitrypsin. Those scheduled trials have been limited by the availability of product. Investigation of alternate delivery systems continues, as does investigation of gene-based therapies.

Five. The NIH should support the continued evaluation of the use and appropriate dose of intravenous immunoglobulins for indication where it benefits, and similarly, dose trials have been limited by availability, and there was that clinical comparability workshop from the FDA in October of 2000.

Six. The industry should work with the FDA to expand capacity sufficient to meet anticipated demand for plasma derivatives, and industry members have announced plans to expand capacity.

And industry and government should jointly explore the antitrust implication of efforts to share data in order to prevent shortages. This was done to some extent, but there was some concern however in the question of the projection of demand.

In August of '98 the Advisory Committee recommended that HHS take steps to accelerate the transition from plasma derivatives to the recombinant analogs. This is very similar to what we already discussed a few minutes ago. The Advisory also recommended that HHS support research, develop alternatives to plasma-based technologies for other diseases, such as immunodeficiencies, alpha1-antitrypsin and von Willenbrand's disease, and this research does continue to be supported.

The Advisory Committee recommends that the Department of HHS maintain, and as necessary, expand or intensify surveillance of blood donors and recipients for existing and emerging transmissible diseases. And this is an ongoing issue that is frequently addressed by the Department and also specifically by this Committee.

The Advisory Committee directs its staff to develop options to be presented to the Blood Safety Director for the creation of a sentinel system to monitor production, demand and utilization of blood products, and to create projections for future demand. I think it's fair to say that several systems have been in development or operating within a department, and studies are under way to improve the effectiveness of this monitoring.

Five. The Advisory Committee recommends that the Secretary of Health and Human Services direct the Healthcare Financing Administration and other appropriate agencies to explore strategies to ensure that all patients have access to adequate reimbursement for recombinant technologies and report to this committee in a timely manner. Discussion over reimbursement issues continue at many levels. Reimbursement for outpatient use of plasma derivatives was specified in the April 7, 2000 HCFA final rule on hospital outpatient and prospective payment systems.

The Advisory Committee recommended the secretary examine innovative responses, including regulating the import and export of plasma and finished products in order to ensure a safe and adequate supply of plasma derivatives and recombinant products for American use.

The Advisory Committee encouraged further efforts to develop and communicate standards for the prophylactic and therapeutic use of clotting factors and other blood derivatives. And clinical trials are needed, and they're dependent on particular product and availability, and the Department remains receptive to such initiatives. There is a typo here. This number 7 was duplicated/

The Advisory Committee urges the Secretary to convene a meeting of manufacturers of plasma derivatives and their recombinant analogs, to discuss strategies for distribution in light of shortage. Action on this particular recommendation was deferred as it was thought that it might be anti-competitive.

November '98. The Secretary of HHS, she recommended legislation that would lower barriers to the use of Federal databases for locating individuals at risk of hep-C. This particular recommendation was received by the Department, but no specific action was taken.

The Department of HHS should allocate sufficient additional resources to permit the CDC to work with state and local health departments to facilitate education, testing and referral programs for individuals at risk of hep-C, and in the fiscal year 2000, CDC budgeted $12.9 million for hepatitis C activities.

HHS should investigate supplemental sources of financial support to facilitate prompt completion of targeted lookback for individuals at risk of transfusion transmitted hep-C. Discussion of reimbursement issues continue at many levels. Reimbursement for outpatient use is specified in the HCFA Rule on outpatient prospective payment, but I don't think that that one really addresses that particular recommendation. We need a better answer on that one.

Four. HCFA should remove financial barriers to testing individuals identified by current government standards at being at risk. March '99 HCFA issued Program Memorandum 804 which clarified its coverage policy on HCV testing.

Five. The Secretary should take all necessary steps to ensure completion of current lookback programs within current recommended time frames, and the agency, FDA Commissioner Henney in March 2000, reaffirmed the commitment to enforce this issue. The Advisory Committee on Blood Safety supported recommendations 1A and 3 of the Senate's report to the House Committee on Government Reform and Oversight, and this was noted by the Department.

The current targeted lookback program should be expanded to include recipients of blood from donors subsequently identified as repeat reactive by a single EIA screening test that was licensed in 1990. This recommendation was noted by the Department. Implementation of that particular motion should be deferred until the Public Health Service had an opportunity to review and to present options for its implementation evaluation of the Advisory Committee at its next meeting.

Probably ought to have some more follow up on what the status of the lookback is, and maybe we could get that from, some statement from ABC on the status of the HCV lookback that we can put in here.

7DR. BIANCO: Mark, Celso Bianco. It's not entirely consistent with the previous, earlier, that says that there were guidances that were issued and all that. So they should match in a certain way, the two meetings on HCV.

DR. BRECHER: Well, it gets worse, because we talk about it again in the next meeting.

DR. BIANCO: I know.

DR. BRECHER: And maybe we should just refer all these hepatitis C recommendations to one summary statement. This is what actually happened.

DR. BIANCO: Actually at the bottom of each one of the issues that was read, maybe you could have a short paragraph, kind of the current status of each one of these issues.

DR. BRECHER: Yes. Because many of these issues, as you can see, they come up from meeting to meeting, and it may be simpler to just say in the end, this is what actually happened.

So again, in '99, January, the Advisory Committee recommended targeted lookback on repeat EIAs with some more specific parameters, and in June '97 there was a guidance industry from the FDA that talked about many of these areas.

Two. The Advisory believed that in light of the scope of hepatitis C, lookback current funding was inadequate for notification, testing, counseling, education and therapy. They urged the Secretary to immediately take measures to increase funding. Discussion over reimbursement issues continue.

We see that a lot when we ask people to cough up money for programs. There are discussions, but there's usually not a whole lot of action. That's a Chairman editorial comment.

[Laughter.]

DR. BRECHER: But there was a conference entitled: Identifying and Managing Transfused Patients for Hepatitis C in the 21st Century, which was held in Washington in February 2000.

Three. The Advisory Committee urges the Secretary to consider providing appropriate support and resources for blood centers and hospitals, both public and private to conduct the lookback activities, and again, similar response. Discussion continues.

CAPTAIN McMURTRY: Let me add one thing to that. There was recently an update on the hepatitis C question about a couple of weeks ago, and one of the issues that arose in the Secretary's office was how much money did the Department provide for these activities? Clearly the answer was none. And there was some concern in the Secretary's office that this had--that--the word they used was "edict"--had gone out with no support from the Department. So I don't know what that means in the long term, but at least the Department is aware that this went out, was a burden on blood collection agencies, and that we did nothing to support it financially.

DR. BRECHER: I'm sure the blood collection community is grateful that at least the issue's been raised again, and there is some regret that there wasn't some funding.

That takes us to April 1999. This must have been a short meeting because there was only one resolution here. The Advisory Committee recommended that blood products obtained from persons with hemochromatosis carry no increased risk, and basically it concluded that the Advisory Committee recognized the need for--to incentive for donation due to financial consideration. For this reason, HHS should create policies that illuminate incentives to seek donation for purpose of phlebotomy. Thus undue incentives are removed. The Department should create policies that eliminate barriers to using this resource.

In August '99, the FDA Commissioner wrote the Surgeon General to describe actions to implement this recommendation. A guidance for industry was prepared. And I think it's fair to say that this is still in flux in this country. Some blood centers are collecting hemochromatosis donors and some continue to not.

DR. HOOTS: Keith Hoots. But there is the exemption that was implemented after this recommendation, wasn't there? I mean--yes, Jay?

DR. EPSTEIN: FDA took the position that it would approve variances to waive the requirement that the medical condition of the donor be labeled on the unit, and to waive the restriction for collection only once every eight weeks. In cases where the donor had a documented hemochromatosis and where there were no fees attached to the phlebotomy.

DR. BRECHER: Similarly, the American Association of Blood Banks and their Standards Committee reworded their standards to allow for these types of donations.

DR. EPSTEIN: The part that's in flux is that it would require rule-making to remove the need to request variances, and the FDA is well aware of that.

DR. BRECHER: Thank you, Jay.

August '99 Advisory Committee concurred with the guidelines put forth on variant CJD. Donor exclusion, it was noted by the Department, the Committee requested that it be advised at each meeting about the status of the British donor deferral policy and its impact. This is noted by the Department. I think it's fair to say that sporadically we've re-reviewed this issue at this Committee.

The Advisory Committee recommended the Secretary of Health and Human Services exercise her existing statutory authority to exclude plasma-based therapies, their biotechnology analogs, and blood therapeutic alternatives from the definition of covered OPT services under Medicare hospital outpatient department prospective payment system. The Committee further recommended that the Medicare program separately reimbursed for these therapies when furnished in a hospital outpatient department including emergency rooms on a reasonable basis. And again, discussion over reimbursement issues continue at many levels, and some of this was covered in the HCFA final rule on hospital outpatient prospective payment.

The Advisory Committee recommended that the Secretary use her existing authority to exclude therapies under APC 369 from the prospective payment program for hospital outpatient services and reimburse them on a reasonable basis. This one was received by the Department.

The Advisory Committee recommends that the Secretary direct the FDA to construct the HCV lookback in accordance with prior recommendations by the Committee. November '99, FDA guidance HCV lookback was a response to this.

The Advisory Committee recommends that the Secretary work with Congress to seek additional resources to support the introduction maintenance of mandated blood safety measures, and this was received by the Department. And the Advisory Committee continued to be concerned about shortages of intravenous immunoglobulin and alpha1-antitrypsin despite laudable efforts on the part of industry and government, and the Committee supported new as well as continuing efforts to alleviate the shortages. And the Department continues to monitor the situation.

January 2000, the Committee directed the staff to create on the Committee's website a list of key recommendations that the Committee has made in a format that would permit the public to see what progress has been made on implementing each of these recommendations.

While they were somewhat on the website, I can't say that they were easily accessible on the website, and we are now attempting to bring this particular recommendation to closure, and that's what this effort is.

Two, the experience of aviation and other industries support the use in all blood establishments; i.e., blood and plasma collection centers and facilities to provide transfusion services of a confidential, nonpunitive system for the management of error and accidents not subject to regulatory requirements.

The FDA has examined its current guidance to determine if additional recommendations were needed to address investigational reporting of errors, and we'll talk about this as it pertains to some of the recommendations below as well.

All blood establishments should have a quality assurance program, and there is an FDA final rule on this issue. Quality assurance programs in all blood establishments should capture, analyze and respond to data and all deviations from established procedures, as well as errors and accidents, independent of whether the affected units were distributed or caused adverse medical events. This is thought or understood to be a component of a good manufacturing practice.

FDA should extend its current error and accident reporting requirements to apply to all blood establishments, including hospital transfusion services, rather than just licensed establishments, and this was included in the final rule that we've already talked about.

In order to facilitate improved transfusion safety for errors and accidents not subject to regulatory requirements, there should be established outside of the regulatory framework an effective, confidential nonpunitive system for the accumulation, analysis, and dissemination of data from all blood establishment quality assurance programs. This was referred back to the Committee for further consideration.

Industry and government should be encouraged to facilitate the evaluation and implementation of devices that promise to prevent misidentification of blood products and/or patients. FDA is evaluating its application process for product and recipient identification devices to ensure efficient handling of these applications. This is I think a problem that the industry continues to struggle with, as does the pharmacy industry.

April 2000. Advisory Committee recommended establishment and implementation of a national reporting and analysis system for transfusion medicine as a basis for action to reduce and prevent morbidity and mortality due to human and system error. The Advisory Committee was impressed with the accomplishments of the error reporting correction systems that have been developed to improve air travel by the aviation industry and the federal regulatory agencies within the system. This particular recommendation or acknowledgement was received by the Department.

The Advisory Committee acknowledged the efforts of the FDA, working with the blood and plasma collection industries in reducing errors and accidents and is favorably impressed with the results to date of the MERS-TM Error Management System. While a great deal has been accomplished, the Committee now believes that the opportunity exists to apply these principles to transfusion medicine.

Error Management should acknowledge the right of patients to know of any risk or harm suffered as a consequence of any error or accident related to blood products. At the same time, there should be statutory protection from disclosure for voluntary report information and of quality assurance activities that are not associated with potential or actual harm, provided that the information is also not associated with reckless or intentional harmful acts.

These Error Management Systems should complement, and not replace, current regulatory activities, notably, but not exclusively, in the area of product safety.

All analysis of collected data should be made available in a timely manner to regulatory agencies, national transfusion medicine surveillance programs and other participants in the reporting system. Again, received by the Department.

It was asked that Congress appropriate sufficient funds to develop these systems for an infrastructure, to support and maintain them in the fiscal year 2001, that Congress should stipulate that these funds should not be reallocated for other purposes and that no other funding should be reduced because of the availability of these funds. That's sort of wishful thinking, wasn't it?

[Laughter.]

DR. BRECHER: Funds necessary to maintain these systems should be appropriated annually. This was received by the Department.

Two, there was a small, but non-zero risk associated with the use of blood products or plasma derivatives that cannot be eliminated with current technologies.

The Advisory Committee, therefore, supported the prior recommendation of the IOM, and of others, that a national system to compensate a prospective national system for recipients of injuries or death caused by blood products or plasma derivatives not associated with a reckless or intentionally harmful act should be enacted and funded by Congress.

The Department continues to feel that compensation issues are the responsibility of Congress. However, it stands ready to assist Congress as it considers such recommendations in the future.

The Advisory Committee is dedicated to ensuring patient access to safe blood products and services. And whereas the Committee recognizes that fair, accurate, and timely reimbursement, including Medicare for blood-related therapies is critical to ensuring patient access to the safest possible blood--boy, someone liked a lot of commas in this sentence--the Advisory Committee, consistent with its prior recommendations, recommends that the Secretary and Congress support legislation to ensure fair and accurate reimbursement, through inpatient blood-related products and services.

Such legislation should provide sufficient funding to account for increased blood-related products, including those associated with new blood safety measures and require that these costs be reflected in annual updates of inpatient diagnosis-related groups.

The Department's reaction to this recommendation was favorable. However, the current view is that a comparable policy on reimbursement for inpatient blood and blood products use would require some type of congressional action, which has not been forthcoming.

The Committee recommended that HCFA promptly distribute guidelines for coding and billing of blood and plasma products to all entities covered by the outpatient prospective payment rule. Furthermore, the Committee urged HCFA to work with stakeholders, including consumers, outpatient departments and manufacturers to capture actual utilization and billing data, to be used to establish a permanent payment system for blood derivatives administered in outpatient settings. HCFA stated that it would do so.

Five, the Committee recognized the significant economic issues currently affecting the blood system, and the Committee seeks to review the role of various considerations and decisionmaking related to new and existing blood safety measures. The Committee was to meet in August 2000 to consider that issue.

So we go to August 2000, and our recommendations in August.

CAPTAIN McMURTRY: Well, I'm going to have to ask the Committee's help with this one. It was not clear to me that there were actual recommendations made. I read the transcripts, couldn't find an actual recommendation. Clearly, without a recommendation, I don't know what sort of follow-up there were. It was a time of flux in our office then, and I don't have a record of what happened in August of 2000. It's not in the file. So if anybody knows, please let me know.

DR. BRECHER: This brought us to January 2001, where universal leukoreduction was reviewed, and it was recommended that this be implemented as soon as possible. The Department has taken no action on this recommendation. So what are the current estimates for the percent of leukoreduction in this country?

MR. BIANCO: For platelets, it's pretty close to or--

DR. BRECHER: Apheresis platelets.

MR. BIANCO: Apheresis platelets, it's pretty close to 100 percent.

For random donor platelets from old blood, it's hard to have a figure because this is done at the hospital lab in general. But for red blood cells, I don't know somebody from the Red Cross here, but the Red Cross I believe has close to 100-percent leukoreduction of red blood cells. Among the ABC centers, about 60 percent of the red blood cells that are distributed are leukoreduced. So you could average for the country, it's about 80 percent of the red cells distributed.

DR. BRECHER: That's helpful. We can at least put that in as, in effect, what has happened. Of course, for platelet dosing, apheresis platelets I think make up 60 percent of doses currently.

MR. BIANCO: I would assume so.

DR. BRECHER: Yes. In regard to leukoreduction, the Advisory Committee is concerned about the availability of blood and the resources necessary to implement universal leukoreduction. For these reasons, the Advisory Committee recommended that the actions of the Department of Health and Human Services should strive to minimize the impact on supply, assure adequate funding for this effort, issue a regulation to implement universal leukoreduction to address these concerns and report to the Advisory Committee on a regular basis. No action was taken on this recommendation.

The Committee recommended the Secretary appoint a representative to HCFA as a nonvoting government representative to the Advisory Committee. As we'll hear later, the new charter that was signed in October 2002 does call for a member from CMS.

Given the unresolved scientific issues in the field, the Advisory Committee supports continued research in the effectiveness of universal leukoreduction. No action by the Department.

In the above resolutions, the word "leukoreduction" was intended to mean prestorage, and the resolution is referred to nonleukocyte cellular blood components.

April 2001. The Advisory Committee recognized the importance of international issues of blood safety and availability and the importance to public health in the U.S. The Advisory Committee endorsed the present activities of government agencies in this area and supports the enhancement of these activities. Specifically, the Committee encouraged the HHS to foster research, training and standard-setting activities in international blood safety, including development and transfer of appropriate technologies for the developing world. The Department has not taken any specific action on this recommendation.

The Advisory Committee supports the establishment of a mechanism to identify priorities and coordinate the exchange of information and activities among government and appropriate nongovernment agencies in the U.S. This effort should include appropriate linkages of international organizations and ongoing monitoring of these issues. Again, no specific action by the Department.

Whereas, patient access to a safe and available blood supply is a public health priority, the Committee recommended that the Secretary and Congress, A, ensure appropriate office within the Department has the responsibility to facilitate gathering and disseminating of national blood collection and distribution utilization data, analysis and development of analytical models to predict shortages.

Moreover, adequate federal dollars should be provided to support collection, analysis and distribution of these critical public health data. Specifically, the following actions should be addressed:

One, assign responsibility;

Two, support programs to develop data, assure data is collected and available to the public;

Three, encourage collaboration of blood collection centers for the purpose of identifying and addressing areas of short supply; and,

Four, encourage collaboration of plasma manufacturers for the purpose of identifying and addressing areas of short supply.

This area is being addressed. Actually, a lot of effort from the Office of the Advisory Committee has gone into this within the last two years.

Do you want to say anything more about that, Mac?

CAPTAIN McMURTRY: No.

DR. BRECHER: Okay. Thanks.

[Laughter.]

DR. BRECHER: B, support a program of public and physician education designed to improve blood and blood product donation and utilization throughout the U.S. and encourage support for such programs through the HHS.

The Department hasn't taken any specific action, but you'll see when we come back to it, the HHS has started to take a leadership role in advocating blood donation.

January 2002, a year ago. We mainly addressed emergency responses by the blood banking industry. Basically, we endorsed the AABB Interorganizational Task Force on Domestic Disasters and Acts of Terrorism as the coordinating center for the national response of the blood community. All of the other recommendations basically revolve around that, including some changes to the federal response plan.

Although this was received, it has moved forward.

CAPTAIN McMURTRY: It has moved forward, particularly in regard to Recommendation Bank there, that the responsibility under EFS 8 move to the AABB Interorganizational Task Force. The Department, while it was my understanding when I researched this that it was not complete, the Department was moving in that direction, and they would accomplish that.

DR. BRECHER: That was a quick set of resolutions to go through. It's easy when you've been at the meeting.

September 2002. Whereas, fair payment to hospitals, and blood, and blood components, transfusion service and transfusion laboratories is essential to ensure that Medicare patients have access to the best possible care, the Advisory Committee recommended that the Secretary direct CMS to establish 2003 Medicare hospital outpatient prospective payment systems for blood and blood components, transfusion services and laboratory procedures based on current-year acquisition and actual total costs for providing such products and services, rather than hospital outpatient claims from previous years. Received by the Department.

A similar recommendation on adequate reimbursement for plasma-derived therapies and the recombinant analogues was number two. Similarly, it was received by the Department.

The Department should provide increased public awareness by the ongoing need for routine blood donation by healthy persons via, A, periodic public service announcements, visible blood donations by top officials and paid advertising campaigns, funding of demonstration projects to optimize use of education and other behavior-influencing approaches, supporting specific initiatives to encourage routine donations by young persons and minorities as part of the general message of a healthy lifestyle and community support, and, D, play a leading role in increasing participation of federal employees in donating blood.

And the Department did develop a program entitled, "Give Thanks, Give Life, Give Twice," and is scheduled to be implemented or was implemented--Mac?

CAPTAIN McMURTRY: It was implemented, and there was a subsequent part of the program where the Secretary wanted the Department to step up to the line and donate as much blood as possible.

Then, the Secretary--I have to say to you I was curious whether it was going to happen, but, in fact, it has because I've gotten calls from other Departments. He has subsequently challenged the other Department Secretaries to meet the level of donation within the Department of Health and Human Services. That has actually started, and it's his plan, I understand later on in the year, to challenge industry leaders then to match the donation level of the government. So this is an ongoing plan.

DR. BRECHER: Very good. Thank you, Mac. I think we accomplished something there.

DHHS should maintain or increase funded support for blood supply monitoring, and this issue is currently being addressed within the Department.

Five, DHHS should support activities to improve management of blood inventories, defining the role of liquid or frozen reserves, integration of supply forecasting strategies directed to correct imbalances in supply need and strategies to facilitate movement of blood from areas of surplus to areas of shortage, and this was receive by the Department. I know the Department is looking at this.

CAPTAIN McMURTRY: That's correct.

DR. BRECHER: I hope this wasn't too painful. I think this is an important charge of this Committee that we get this grid as complete as possible and out on the website so that it is available to the public. I think, overall, when you look back, while some of the recommendations little or no action was taken, I think, on balance, this Committee has done pretty well would be my assessment.

Keith?

DR. HOOTS: It struck me, after listening to Paul's historical review of where we've been, and then going through these in order, that, clearly, not surprisingly, resource allocation quickly jumps to the top of the impediment to what we would like to see happen.

I don't have any obviously great solutions to this. It seems like that since, at least in the initiation of this Advisory Committee, Congress did have some sort of imprimatur for its creation that perhaps, at least at some point, we might discuss how, obviously, we advise the Secretary of Health, and that's clearly what our mandate is, but we might want to at least talk about strategies to see how the information about these recommendations get disseminated more widely to perhaps help the Secretary because, obviously, he has not unlimited resources, and obviously they're contracting. But if he has to go and prioritize within existing resources, without at least some exigency from outside, it may be very difficult for some of these things to ever happen.

But if other members of the government, outside of the Secretary's HHS Office, were aware of the importance, perhaps, maybe it would--I don't know. I don't have any great strategy to do this, but it just seems like that's the recurrent theme.

DR. BRECHER: That may be something we might discuss when Dr. Slater comes a bit later.

Ed?

DR. GOMPERTS: Ed Gomperts.

Just looking through this substantial body of recommendations and responses, the Committee has been going for about five-and-a-half years, and it's appropriate that the Committee lookback at its original charge and also what has been accomplished.

Very superficially, as you went through this and reconsidered a number of points here, broadly speaking, there are links over the years between one Committee deliberation, recommendations, et cetera, and quite often there's follow-up in subsequent Committee and subsequent recommendations.

Of course, we've dealt with supply, and we've also dealt with the availability issue again and again looking at different topics. It would be useful, certainly from my point of view, to look back over the years and follow through the links. Some of the issues clearly have been dealt with and closed. The HCV lookback is obvious.

The new variant CJD issue was dealt with, but, to some extent, quiescent, but might become an issue in the future. Just where do we stand with that?

The availability issues, again, we looked at certainly the plasma derivatives, and by and large what is the status today? And, of course, the reimbursement issue, where does that stand.

So it may well be that some topics that were addressed three years ago could well still be very pertinent, and it may be an idea to relook at them from the point of view of status.

So, as we go through this and identify the particular recommendation, the response, current status, it's probably a good idea, also, to bring it back to the Committee to deliberate as to the need for relooking at these things with potentially subsequent recommendations.

DR. BRECHER: We actually have formed an Agenda Subcommittee to try to plan for the future for meetings, and, tentatively, for the next meeting we were talking about discussing national blood policy. Whereas, reimbursement would be a major component of that, and so I think that that's right.

We probably need to bring to closure those early meetings on hepatitis C lookback and probably ought to have a summary of what actually happened, and I think we can certainly do that as part of the next meeting as well.

DR. GOMPERTS: Yes, there's a substantially history that's been established, and it's good to look back and to start tying things together.

DR. DAVEY: Mark?

DR. BRECHER: Yes, Rick?

DR. DAVEY: Rick Davey.

First, I want to commend Mac and the staff. This has been a very useful, interesting historical perspective. I don't know what grade to give the Committee on how we've done, maybe a B, but we've certainly accomplished some good stuff.

DR. BRECHER: Is that a B for blood?

[Laughter.]

DR. DAVEY: B for blood.

Obviously, there are other Advisory Committees, BPAC and TSEAC, that have addressed similar issues. And it might be useful, in pulling together this summary, to occasionally, when appropriate, cross-reference what has been addressed and recommended by these other Advisory Committees because there's often considerable overlap in what the committees address, and occasionally the recommendations may not be entirely consistent or, on other occasions, they may be very complementary.

But I think it would be useful for this Committee, as kind of the oversight committee, if you will, the Advisory Committee to the Secretary, that we have a full understanding, where appropriate, of what the other two key Advisory Committees that have addressed these issues, where they've stood on these particular issues.

DR. BRECHER: Mark, I'd like to echo Rick's comment. I think this is a great work product.

Just a couple of things for consideration. I wonder if it would be useful to take each of these recommendations and try and link them back to the charter just to show that there's some kind of alignment between what the Committee is actually doing and what it was chartered to do just to kind of close the loop there.

As another question, I was wondering if you have a date in mind, if you're giving us an assignment, you want comments back by a certain date in order to try and facilitate this process along so we'll have a final document to look at next time.

DR. BRECHER: Yes, your homework, Committee members, and there is a huge amount of expertise and experience on this Committee, is to please look at this very carefully. Let's make this as accurate a document as we possibly can.

I would ask that you get all comments back to Mac within a month, let's say by March 1st. We'll then integrate all of those comments and distribute them. I'd like to have the next draft available by the next meeting, and at that time, we'll get it to you before the meeting. I apologize that this came late.

Mary?

DR. CHAMBERLAND: Mary Chamberland.

One thing I think that we're going to have to do, and I agree with taking a careful look at this and getting comments back by March 1st, one thing that we're going to have to try and struggle with is this balancing act between the document as it's structured now I think is to, with the intent of sort of at a glance to be able to tell you what the recommendation was and what the action was.

I have some concern that for several of these recommendations, the appearance in the result column of no action is really an inaccurate representation of what's happening within the PHS. For example, the first recommendation for April 29, 2001, had to do with international blood safety-related activities and encouraging the Department to foster research, training, standard setting, et cetera, and the response is Department has taken no action.

Clearly, agencies like CDC, the NIH have very extensive programs that relate to international blood safety and support for these et cetera. So I don't think what we want to have is this document then become some sort of summation of the PHS activities in these pertinent areas, but by the same token, it's not accurate to say that there's no action. So I think we might have to struggle a little bit about these responses.

There were similar things that had to do with surveillance systems for CJD, for emerging infectious disease agents, et cetera. A lot of those have been developed. Actually, some of them are quite mature now, speaking for some that come out of the CDC. So I think maybe we might want to have a little bit of guidance as to how we want to approach this because this could then become some voluminous document, and I don't think that's the intent here.

But by the same token, I think it's misleading to give the impression that not a lot has been done, when in point of fact, a lot of the PHS agencies, sort of in parallel with the Committee, have been working in these ares to develop and implement a number of activities.

DR. BRECHER: I think that's a very good comment, Mary. I agree with you completely. I think we strive to be succinct, and we can link out to many of those other sites, if the Committee members could provide us the pertinent links. That way I think we can be short, but still informative.

Jay?

DR. EPSTEIN: I want to come back to the point that Ed Gomperts was making, that many of the issues at different meetings are, in fact, linked thematically. I'm just wondering whether it would not be more useful, as a public communication, to summarize this work thematically, rather than recommendation line-by-line.

I think, to get back comments in a month line-by-line and fix all errors makes good sense, but I think we would have a better summary if we had the theme, a summary of all recommendations that were made over time, and then a discussion of the responses that have been made, both by government and the private sector on the issue because I think that the line-by-line analysis is too simplistic.

It ignores the fact that the actions taken by government and the private sector may not be in direct response to the recommendation, but may reflect other inputs and influences, and I think that we'll get further down a path of useful communication if, instead of pretending that it's a one-to-one relationship, we have instead a description of the issue, a description of the recommendations, and a description of the events that have transpired because I think that will then somewhat mitigate against a simplistic one-to-one interpretation which would not be correct.

DR. BRECHER: Yes, I think that's a very interesting alternative approach. We could have thematic approaches for HCV lookback, errors, blood supply, reimbursement.

We're here to do the Committee's bidding. And so I guess what I would ask the Committee, what is it that the Committee would like us to do?

MR. BIANCO: Yes, I want to support--Celso Bianco--very much what Jay said.

You have the impression, because a lot of the sentences, recommendation was received by the Department or things like that, they give a misimpression that the field did not evolve, and we had a tremendous change in the last five years in many of those areas.

I think that the Committee was, even if I wasn't here, the Committee was instrumental in bringing and raising the awareness, so I missed the opportunity to be part of it, but I watched it, and that was very, very important and I want it to be recognized.

DR. KUHN: Dana Kuhn. I think if the intent of us as a Committee is to review all of this information and to put it on a website where the public can see it and see what kind of progress we have made over the years, it's going to have to be simplistic enough for a citizen to be able to read and understand exactly what's happened.

But I do concur with the Committee that we should have it in a sense of being thematic, seeing what recommendations, and I think there has to be a little bit more detail, like the past recommendations we just had at the last meeting. When I read the letter that Dr. Slater wrote to Mark, there was some very strong comments made in there like, "I will recommend. I will contact," the CMS and so on and so forth, where in this document it just says, "received," the recommendation was received.

So I think there has to be more clarification on a little bit more of what happened because if people read it was received, that might connote that nothing was done, but there has been something done.

DR. BRECHER: So what is the sense of the Committee?

Mike?

COLONEL FITZPATRICK: I think if we relate back to what Paul brought about as the historical perspective, what we have here is more of a table to follow, like the minutes of Committee meetings, what's open, what hasn't been accomplished, what has been. But to communicate the accomplishments or the structure of the committee, what's been happening to the public, we have the IOM study that created the Committee, we have a charter which are both relatively thematic, and then we have resolutions that have recurring themes.

So I think the thematic idea is essential, and as Dr. Goodman said, there's really two constraints; one is resource allocation, the other overall constraint is supply. Every recommendation, every new deferral, everything that has been considered by either BPAC or this Committee has been constrained by its impact on supply or perceived impact on supply.

And if we go back to the IOM study as to why the industry and the government dealt with HIV the way it did, a lot of that was perceived impact on supply. And so I think if we have broad, general themes and indicate the progress of the Committee to impact that relating back to the IOM study, we'd be able to show to the public the progress that has been made to not prevent errors because it's easy in hindsight to say there were errors, but how to change the way we deal with risks to the health of the public through blood transfusion.

I think, thematically, you may want to portray it that way, but you may want, for purposes of clarity to the Committee as to where they're going, provide them something like this table so that you have an idea from meeting to meeting what's following through, and then you have a broad, general overview thematically of the progress of the Committee since the IOM study.

DR. BRECHER: Dr. Penner?

DR. PENNER: As I see it, the weakness of the document relates to its failure to provide the responses and that it hasn't been developed, and the follow-up has not been present for a number of these items that we've considered over the years, particularly the first item that we covered, which was the hepatitis C lookback. Despite the fact that it was reexamined on a number and revisited on a number of occasions, we have no idea of any significant accomplishments in that area because we have not had any update to see what has occurred.

DR. BRECHER: Let's take a vote of the Committee. I think the basic question before is, well, I think we all agree that there has to be some report card of what's happened, and then we can either do it, basically, as line items, as outlined here, or in broad, thematic strokes.

So all those who would prefer that we reconfigure this in a thematic approach, please raise your hands.

DR. LINDEN: Can you tell me who is the target audience for this.

DR. BRECHER: The public. I think this is to educate the public about what the Committee has accomplished.

DR. KUHN: Are you talking about thematic, with what the Colonel just said about linking it back to the charter?

DR. BRECHER: I was thinking more in terms of the major themes that have run through these meetings, such as supply, errors, HCV lookback, those kind of themes.

MR. WALSH: Mr. Chairman--Walsh--I agree with the thematic approach. I think that would be the most constructive and understandable for the general public, but I think it would also be beneficial to complete this analysis in the sense of making it more accurate and more complete on a line-item basis, and then utilize that as a background for the thematic presentation.

DR. BRECHER: Sort of do both.

MR. WALSH: Yes.

DR. BRECHER: So we now have three choices: line item, themes or do both.

All of those in favor of doing both, please raise your hands high.

[Show of hands.]

DR. BRECHER: I think that's clearly the majority. We will do both.

We're running a little ahead of schedule, but why don't we take our break now, and we'll reconvene at 10:30.

[Recess.]

DR. BRECHER: If everyone could take their seats, we will reconvene. We're going to restart.

Our first speaker in this second part of the morning is Jon Moreno, University of Virginia, talking about ethical considerations of medical decisions.

Jon?

DR. MORENO: Thank you. I want to thank the members of the Advisory Committee for giving me the opportunity to talk to you this morning.

When Mac called me a couple of weeks ago to ask me if I would do this, my first reaction was that I really had nothing to say about this that wasn't painfully obvious and that I ought to decline. In a few minutes, you may well decide that my first intuition was the correct one.

Nonetheless, since I paid to rush in where supernatural creatures fear to tread, the more I thought about the subject matter, the more interested I became and the more complicated, it seemed to me, it was.

I want to say that the way that this topic was framed by Mac, and I suppose by others as well, was, well, really, in the face of a matter of grave public concern, partly media driven, to which, therefore, elected officials feel the need to weigh in, taking, as an example, the West Nile Virus experience, how in the face of that kind of pressure and the need to satisfy public concern, how can people in authority, who are supposed to be experts and professionals, how can they continue to exercise their expertise and continue to focus on ongoing chronic, continuing public health problems, while at the same time being responsive to public concerns.

So one of my first reactions was, damnit, they ought to just get some backbone and do it, and they don't really need anybody like me to come in and tell them to do it, but then I started talking to people about this, and they said, "Well, I think somebody like you ought to come in who is disinterested and unburdened by a lot of knowledge about blood and the way the system works," and so I've decided to do this rather eclectic presentation that I put together the last couple of weeks, and really perhaps it ought to be called ethical, and philosophical and historical considerations as much as ethical considerations.

But this is sort of roughly the way I'm going to approach the issue:

First, by putting some facts on the table that come from several of you, actually, in your publications--facts that are as well known, better known to you, certainly, than they are to me; and then talk a little bit about what I call creeping precautionism as a reaction to some of these recent concerns; and conclude with a little disquisition on what I call the burdens of expertise, involving the notion of fiduciary knowledge. That's the trust that resides in you, as experts, that people like me reside in you to protect me from things I don't understand and to keep a balanced view of matters, the virtue of equanimity; and then a little reminder from Philosophy 101 about where the idea of expertise comes from in the Western tradition, and I'm actually going to conclude by making some historical remarks about the role of scientific advisory committees in a democracy.

First, just some facts that I've gathered from Mark, as well as others, with respect to the ongoing continuing problem of bacterial contamination in the blood supply. This is not data that you're unfamiliar with, of course. I was struck by the observation that perhaps one patient a day develops a life-threatening infection due to bacterial contamination, and that it's vastly more likely to transmit infection than HIV, hepatitis C or West Nile and that some of the sickest people in our hospitals are the most likely to be recipients of these units.

There seems to be consensus in your community that contamination-related transfusion reactions have been continuing in the past two decades, but the number of deaths that are reported to the FDA each year has been said by Jim MacPherson to be probably the tip of the iceberg; namely, about 10 to 15 a year, and I would actually challenge the Advisory Committee to examine the reporting problem and figure out ways of ameliorating it because it seems to me that we do need more data on the actual number of deaths from bacterial contamination than we seem to be getting.

Now, I know that there's going to be disagreement around this table about whether these are examples of what I'm going to be calling in a minute "creeping precautionism" in blood services, and I accept that there is going to be disagreement. Yet, a number of people I've spoken to in the blood world and in public health, more generally, have spontaneously given me these examples when I've asked for them.

I've asked colleagues in different parts of the country, in different fields, what are some examples in which we might have actually gone too far in recent years and been too cautious, been to risk averse, in other words. And the examples that come up, in fact, have already been mentioned this morning, interestingly; the deferral of people who lived in Europe for CJD, and p24 antigen testing for HIV.

Again, I'm not here to assert that these are examples of excessive risk aversion or what I call creeping precautionism, but let's suppose that they are, just for the sake of argument. Humor a visitor.

I think part of what's going on here might be that the original precautionary principle articulated by Europeans in the last 10 years or so has been taken, to some extent, out of context. Here is a sample statement from the European Environment Agency that articulates the precautionary principle, a principle adopted by the U.N. Conference on Environment and Development:

"That in order to protect an environment, a precautionary approach should be widely applied; meaning that where there are threats of serious or irreversible damage to the environment, lack of full scientific certainty should not be used as a reason for postponing cost-effective measures to prevent environmental degradation."

Now, that's a double negative, but you get the point.

Secondly, that the precautionary principle permits a lower level of proof of harm to be used in policymaking whenever the consequences of waiting for higher levels of proof may be very costly and/or irreversible, and I've emphasized the phrase "very costly and/or irreversible," just to show you that again because I want to come back to that. Because I think that the way we interpret this notion of cost and irreversibility is critical with respect to blood services.

Here is another statement, a more recent statement about the Commission that I want to also refer to in a moment, again. This communication that they're talking about makes it clear that the precautionary principle is neither a politicization of science--or at least it should not be a politicization of science--or the acceptance of zero risk, but that it provides a basis for action when science is unable to give a clear answer; namely, preventive action.

Now, I think that the precautionary principle has become, in recent years, a basis of support for a very risk-averse attitude in areas other than the one for which it was originally intended; namely, environmental protection. I think that this has happened partly because the original context of the principle has been torn away in some recent conversations.

Removing the concept or the principle of precautionism from the environmental or ecological context and applying it directly to the public context requires more analysis I think than it's been given. In particular, to take the notion that the possible harms might be very costly and/or irreversible, to take that notion and to imply that even one death is unacceptable is a respectable view, but it's a view that requires defense, and I don't know that it has been adequately defended.

The original notion, again, was that the notion of high cost and irreversibility should be applied to profound climatic change. If we now take that notion and move it into a different area, then I think that transportation of the principle requires more defense than it's gotten among people like us in the last few years. That's not to say that it can't be defended, but I don't think it has been.

Now, of course, precautionism, particularly in the context of blood services, and I actually gave a talk once to the AABB in which I used the term "the blood industry," and some people were offended by that language, so I'm going to say, more neutrally, blood services.

The principle of precautionism, arguably, is supported in this context in light of the HIV experience; that blood services are an especially sensitive area and public trust must be retained in order for the system to work. Obviously, I'm very sensitive to this argument.

But it doesn't follow that a zero-risk philosophy must always be adopted in order to retain public trust. In fact, one could argue that this is a two-edged sword. The other edge of the sword is that the public trust in the expertise of people like you may eventually be eroded if immediate concerns, media-driven concerns, politically-driven concerns, are permitted to eclipse the bigger picture, and that I think, arguably, is, to some extent, what has happened with respect to blood services.

Now, the people sitting around this table, and your colleagues at your institutions, universities, agencies, are burdened by being experts. I want to reflect, for a moment, with you on what it means to be an expert, what it means to have special knowledge.

It means, for one thing, to be a steward of some specialized knowledge that the rest of us don't have, either because we haven't spent all of the time learning it or because we're not equipped, by virtue of our educational background or intellect, to obtain it. The knowledge that you possess is communal, but not everybody in the community can have access to it. You are literally stewards, people like you, are literally stewards of that knowledge.

Experts have what people in ethics called a beneficence-based duty to express their educated opinion; that is to say, the knowledge that you hold on behalf of the wider community is a trust, and we expect you, I, as a nonscientist, expect people like you to express your opinion and, in some cases, be willing to take some hits if you're wrong.

For you to express your opinion is not, it seems to me, an exercise in paternalism. Paternalism is a distorted expression of authority over people. There's nothing in appropriate or distorting about people who actually have some knowledge to make a reasoned, educated judgment, and again that expertise resides in a scientific community and not in individuals

I expect that you're going to talk to your colleagues, that you're going to consult with your colleagues about the judgments that you make so that it's the entire scientific community, upon which I, as a nonscientist, rely for information and ultimately for protection.

Part of what you possess is what the philosopher, Peter Caus, one of my old professors, calls fiduciary knowledge. I trust you, as I trust my doctor in the clinical setting or a lawyer I might consult or my stockbroker, to know some things I don't know. Even though I can never know them, I have confidence in your judgment because I respect you as an expert. I trust your knowledge, I trust that you will advise me honestly.

And even when, as is often the case with our portfolio managers these days, you may turn out to be wrong, I believe that you owe me the responsibility, as someone who has invested in your skill and your expertise, you owe me the responsibility of telling me what you think is the best course of action for me.

Now, to take the hits associated with being an expert requires the possession of an old virtue that hardly anybody ever talks about any more that the old medical philosophers used to talk about, which is the virtue of equanimity. In fact, if you look at the Hippocratic writings, you see that Hippocrates talks about equanimity when the doctor goes into the patient's room, and the patient is suffering and dying, and the family is in agony, and it's so important for the doctor to retain a sense of detachment and judgment in the midst of the chaos that surrounds the doctor.

This is, in fact, a cornerstone of medical professionalism, the virtue of equanimity. I don't expect my doctor to get upset when he reads my chart in front of me. If my doctor starts to get upset, and looks panicky and tears come to his eyes, that doesn't help me.

I expect, in fact, a kind of detachment, a friendly detachment, but a detachment nonetheless. Sir William Osler put this well more than 100 years ago, and he expressed also how experts, like doctors, can take their hits from appearing to be cold and insensitive, when, in fact, they're trying to retain a measure of personal detachment. From its very nature, he wrote, this precious quality, imperturbability, he put it, is liable to be misinterpreted, and the general accusation of hardness so often brought against the profession has here its foundation.

Of course, it's only within a few years of Osler's statement that the profession of public health emerged, and I'd argue that imperturbability, the virtue of equanimity applies as well to people in public health fields as to clinical physicians.

To make this point, in a larger philosophical sense, I want to remind you of the origins of the notion of expertise in our culture. Now, those of you, again, who haven't been reading "Plato's Republic" recently, there's an image in "Plato's Republic" that's very powerful. It's part of our culture, it's part of our language. We're inured to it. We don't even remember it any more.

But it's what is supposed to separate people who really know something from people who don't. And the general image, you might recall from your philosophy course, is that of slaves, shackled in the bottom of a cave from birth. They can't move, they can't look anywhere except at the wall in front of them. There are people carrying objects behind them, in front of a light source, and the shadows of the objects are cast on the wall in front of them.

What's the result? If you ask these people, "Well, what's real in the world," they would say, "Well, these things I see in front of me." In fact, of course, those things that they see in front of them are only shadows.

Well, one day, according to the story, one of these slaves gets free, climbs up to the top of the cave and sees that there's a whole world out there and that, as a matter of fact, what he thought was a real thing was only a shadow, but that there are real objects that are more real than the shadows, that the sun gives light, and therefore that the sun is the source of the good, the source of truth.

He is illuminated. He is illuminated, and he knows now that what he thought was real was not. He's become an expert, and he's become an expert because he's been illuminated by the light of truth. This is the original notion of expertise in Western society.

And when Socrates' students say these are very strange people indeed, this is a very strange situation indeed, Socrates shocks them, the climatic line is, "They are like us." All we see is the shadows.

Now, expertise, particularly scientific expertise, gives people like you the opportunity to see beyond the shadows in a way that I never will. So can we, in a democracy, function with experts? Plato didn't think so. Plato, as a matter of fact, as you might recall, regarded democracy, in its literal Greek meaning, as the rule of the mob, partly because the mob killed Socrates or at least found him guilty of making the lesser the better cause and corrupting the youth of Athens.

Plato did not think, and by the way Aristotle didn't either, the first real observational scientist, that expertise, that people who knew the truth could really function in a democratic context.

And so what your job is, and not to make this too grandiose, but I think it's nonetheless true, the job of scientific advisers in a democracy is to prove that Plato was wrong and that your expertise, while it must bend to public concern, must not break.

And in fact this is a fairly recent experiment; the idea of systematic, scientific advice being given to government. That idea is only about 100 years old. Teddy Roosevelt appointed the first Presidential Advisory Committee, the Country Life Commission, about 100 years ago. It's only since about the 1930s, and since the Roosevelt administration, the second Roosevelt administration, that experts really had a systematic role in policy development, and this is an ongoing experiment, and there's no guarantee that it will succeed.

If it succeeds, it will be because people like you have decided to resist the pressures of the moment and continue to give your best wisdom knowing that you might turn out to be wrong.

So I'll end with Dr. Osler, again, on the equanimity of the expert: "A rare and precious gift is the art of detachment, by which a man..." and presumably a woman "...may so separate himself from a life-long environment..." something like the slaves in Plato's cave, right? "...as to take a panoramic view of the conditions under which he has lived and moved. It frees him from Plato's den long enough to see the realities as they are, the shadows as they appear."

So your job, speaking again as a citizen and as a nonscientist, is to help me look beyond the shadows and to help me to be illuminated.

Thank you very much, Mark. Thank you, Mr. Chairman.

[Applause.]

DR. MORENO: I don't know that there's any questions that could possibly be asked of me, but I'll hang around here in case there are.

[Laughter.]

DR. BRECHER: Thank you, Jon. It was very illuminating.

[Laughter.]

DR. MORENO: Well said.

DR. BRECHER: And I didn't put him on my bacterial stuff.

[Laughter.]

DR. BRECHER: Paul?

DR. McCURDY: One of the things that was recognized, I think, in the IOM report that I summarized earlier was that patients were not taken into consideration and were not included in the equation when decisions were made in the '80s, as to what to do.

At that time, I was a blood center director. I brought together the physicians taking care of hemophilia in the Washington area, asked them if they were interested in shifting to cryoprecipitate as the treatment, rather than concentrate, and they said, no, they did not want to do that. I was prepared to make enough, so they could, but they said, no. They made this decision on behalf of patients, and the whole patient-physician relationship is still evolving from the point where the physician sits up here, and the patient sits down here, and the doctor orders.

Whereas, it's now getting closer to where the doctor discusses and discusses the alternatives and the risks, and I think that's very important to include in that area, in the equation, that this may be a group of experts, but there was a similar group of experts or several groups of experts in 1992/1994 that made decisions on behalf of patients and were seriously criticized. They did their best, they took their shot, and they got shot.

MR. MORENO: I mean, I think you're--what Dr. McCurdy said is quite accurate, and we're still trying to figure out how to address this balance.

My field, bioethics, of course, got started because of, in large measure, concerns about physician paternalism. And nothing I've said, I hope, suggests that we ought to return to the bad old days. Nonetheless, it doesn't seem to me to be paternalistic for people in a position to know more than I know to give a strong recommendation. And to remove it now from the clinical setting to the policy setting, it seems to me even more important that the scientific community, speaking through you, speak with a clear voice about what's best for me, and if I ignore it, I ignore it at my peril. But at least I can't come back to you and say you weren't straight with me and didn't give me the benefit of your best thinking.

DR. BRECHER: Jay Epstein?

DR. EPSTEIN: Well, more or less along the lines that you were just discussing, the question that we face is what lies after the so-called precautionary principle, albeit in the supply. And a lot of energy and effort has gone into trying to craft systems that will somehow come up with perhaps not better answers but better accepted answers. And I just wonder what your thinking is on the nature or characteristic of such processes. What would it look like if we did it right?

MR. MORENO: Well, that wasn't what Mark asked me to talk about.

[Laughter.]

MR. MORENO: I'm not going to pretend, Dr. Epstein, to be an authority on public health systems. My question is this, or my point, I suppose, is this: If people walk away from a meeting like this, if people finish drafting a document in an advisory group like this, and yet have the sense that they haven't been as forceful as they should be about what they think is in the best interests of the society, then I think that would be an earmark of what I've called creeping precautionism. That's the standard that I want to adopt this morning. I'm going to leave it to people who know how to design these systems to fill out the details. I'm not going to go beyond my expertise, having praised expertise in principle this morning.

DR. BRECHER: Dr. Penner?

DR. PENNER: I'll support Paul's comments and perhaps maybe take a slightly different view of the expert's role as we see it right now. That seems to me that we have the responsibility for conveying information so that the public can make educated choices. We can't make the decisions for the public. And that seems to me much different than we've had in the past in the way of approaching situations where we have information and we're not willing to divulge it and make the decision then for those individuals.

DR. BRECHER: Chris, do you want to go first?

MR. HEALEY: Thank you. Chris Healey.

A potential contradiction I see in what you've said is that if we act with equanimity and detach ourselves from our environment to some extent, to exercise expertise in the best interest of society, we almost by definition are going to incur the ire of that society or at least the suspicion of that society because we won't be viewed as being sensitive and engaged to their particular needs.

So one of the challenges--one of the contradictions I see is how do we attain that level of detachment to act appropriately, yet at the same time act within the democracy where we don't incur their ill feelings, ill will.

MR. MORENO: Well, "contradiction" is a fighting word, you know, talking to a philosopher. I think it's a tension, and I think it's an inherent tension. And if people take on the kind of role that professionals take on, then it's an illimitable tension in the role. I don't see a way around it. I think it constantly has to be negotiated.

Now, as an attorney, you undoubtedly have occasion to talk to clients to whom you give advice, and the advice turns out not to be--I'm sure you're an excellent attorney, but it might not turn out in retrospect always to be the best. You've done the best you could. And that's really all that we can ask, but I don't think that there is any easy exit. I think that's part of what it is to be an authority in a subject area which people invest some trust, reside some trust in you. And it's especially hard in a democratic context.

MR. HEALEY: So are we doing our jobs right if people aren't particularly happy with us who--

MR. MORENO: Yeah, I think sometimes you are. But I think it does have to be done with sensitivity and making every effort to reach out and explain to people what the position is. But sometimes the best medicine is--you know, this is heteropathy, not homeopathy. Sometimes it's necessary to take a position that is unpopular, and you're not elected officials so you have the luxury of doing that without worrying about the next cycle, the next election cycle.

DR. BRECHER: Larry?

MR. ALLEN: While I agree with some of the statements that you made and some of the people on the committee have made, I think that when I look at it in one respect, there's a history here that this field is not--we didn't start out with a level playing field and that for certain people makes a difference.

I think for the average person in this country going to the doctor, it's okay if you want to be a spectator in your own health care and let that doctor dictate the path for you. But in many cases, that's not the way it should work. And something you mentioned earlier about we don't expect our doctor to get emotional when he reads our chart, nor at the same time do we expect our doctors or researchers to accept our fate without compassion. And I think there has to be that balance, that understanding within the patients that the doctor--at some point the doctors have to go beyond the norm because of what these people might be dealing with.

MR. MORENO: Absolutely, and nothing I've said should be construed as an argument, again, for old-fashioned paternalism or for lack of compassion. All I've argued is that it is--that the phenomenon that I see happening among physician colleagues these days, which is worrisome, namely, that too often if a patient asks for a recommendation, a doctor will essentially hide behind the principle of autonomy, which, unfortunately, people like me have been teaching for the last 25 years, and say, "Well, I can't make a recommendation; it's your decision. I can't tell you, you're the one; it's not me." And that I think is an example of going too far.

DR. BRECHER: Rick?

DR. DAVEY: Yes, one of your comments certainly resonated with me, that we have to be careful of letting immediate concerns eclipse the bigger picture. Clearly I think in our field we've been--many of us have been concerned about reacting quickly to the problem de jure, whether it's West Nile or vCJD or any number of other issues. And yet when we perhaps want to look at this in the larger context, maybe some of us have difficulty in defining what the bigger picture is. So we're kind of left at the end of the day with a series of responses to immediate concerns without a context of a bigger picture that we can be comfortable with.

I wonder if you might come in on that at all.

MR. MORENO: I mean, I think that's one of the benefits of working in a group, you know, that you have peer support, you have the benefit of colleagues' expertise about related areas, and you have the opportunity to kick back and try to obtain a bigger picture in a social context that's so hard when you're sitting alone in your office.

So I would say that's--you know, the good thing about a committee is that you have people with whom you can reflect. And the bad thing about a committee is that it's a committee. But there are some virtues in the social process, even though they take a lot more time.

DR. LOPES: I should say by way of outset that I'm the person on this committee who's here representing the mob, or at least the mob psychology. I was interested in reading the executive summary of the IOM report that Recommendation 6 said where uncertainties or countervailing public health concerns preclude completely eliminating potential risks, the FDA should encourage and, where necessary, require the blood industry to implement partial solutions that have little risk of causing harm.

This strikes me to be a precautionary principle stated in the medical arena. We have seen on this committee experts in the blood services industry speak not only verbally but also by the actions of their groups in areas like universal leukoreduction where it wasn't--this is a partial solution to a very unclear problem, but there was a lot of thinking there, I think, if I remember correctly, that this was something that would not cause any harm and might do good in application of the precautionary principle.

I'm just wondering whether you think that a suitably phrased precautionary principle could never be relevant in medicine. I just don't see why the environment is different in principle, given that for at least some of the things that we faced, major and irreparable harm has been done in allowing, say, an epidemic like AIDS to go as far as it did.

MR. MORENO: I agree. There's no reason in principle that it couldn't. And perhaps we get into difficulties when we start to think in terms of avoiding all risk. Perhaps it's the notion that we can live in a risk-free world that begins to create trouble. But I absolutely agree with you that, in principle, it should be possible to apply such a concept.

I think that what often has happened, though, as I asserted earlier, is that it's kind of crept up on us without analysis, and that it seems to be the easy way out, that it seems to be the prudent approach, isn't always, it seems to me, the right approach.

MR. SKINNER: What I'm trying to rationalize in my mind is I come to this committee as a layman or as a consumer. I don't come from a medical or a technical background. So my expertise are life experiences and what I've learned along the way. And what I think this committee is supposed to do is to kind of balance that knowledge and power base into equilibrium. And I'm wondering if we don't come and have different roles and if the consumer's role here has a little bit different standard than what was articulated here, at least the approach which we've taken really is the approach of zero tolerance approach and until, you know, the knowledge and power and we're persuaded otherwise to accept something different than zero tolerance. How do you--do you see the roles of committee members different as opposed to what seemed to be kind of one global role that governed the work of the committee?

MR. MORENO: Well, I've been on advisory committees and I've been staff to advisory committees, and I've thought a lot about this very interesting question about the notion of representation on advisory committees, and I'd like to talk to you about that, actually, on another occasion.

But in this case, I guess I--I'm a consumer, too, and I'm a lay person, not a scientist or a physician. And I want to know what the downside is. There's always a downside. Take zero tolerance, something's going to be left out. And I guess I'd want to know what I'm letting myself in for. If I avoid one risk, what am I--what's the possibilities of others? And I would need, again, the benefit of the experts at the table to let me know, you know, what that balance is.

DR. BRECHER: Mike?

COLONEL FITZPATRICK: Just going back to the creep theory and the zero tolerance question takes me back to what I said earlier about supply. The balance this committee and others struggle with is always the impact of harm in the context of there not being enough blood available from the actions that the committee takes or the regulatory body takes on recommendations of the committee.

MR. MORENO: Right.

COLONEL FITZPATRICK: But the perceived application of the principle is to move towards zero risk, and the closer we move toward that, the less impact we make on safety, the more impact we make on availability. And the models that have been presented to predict the impact on availability for each new thing we have incurred have not been correct. When we say we're going to see a 15-percent reduction in donors, we don't see a 15-percent reduction in donors. And we don't have good, factual explanations of why that occurs, but we have observation that it does.

But we have observation now that we have a distinct problem with supply, and I guess one of the questions I have for you is: How do we as a committee measure that irreversible harm to an individual versus the group? And how do we arrive at an acceptable model of--you know, one failure in 5 million for brakes on a car is acceptable. One failure in 12 million for testing for blood appears not to be. How do we balance that?

MR. MORENO: Lots of people have talked about this, as you well know. There's no right answer. There's no algorithm. I think finally it's a political judgment. But it's a political judgment in the grander sense of politics. It's a social judgment, what people in general are comfortable with given the risks on the other side, the availability problem, if we were to know them. And I appreciate that we don't know them too well.

But, again, I think that's--in order for people like me to make a judgment like that, I need information that you can provide. But I think that there is no magic bullet that's going to give us that answer. It is a political judgment, and it may vary, irrationally, from one context, as you mentioned, to another.

DR. HOOTS: You emphasize knowledge in terms of expertise. Mark was talking about coming at it from a different perspective. Is that really what we're striving for rather than knowledge in terms of conferring expertise in bringing to the occasion, decisionmaking, some semblance of wisdom which would reflect both knowledge and experiential impact of exercising of knowledge?

MR. MORENO: Absolutely. Experience counts for a lot in the clinical setting. It counts for a lot in the public health setting and policymaking. The knowledge that a representative of the consumer can bring is the viewpoint of the consumer to make sure that's on the table all the time. That's got to be part of the mix. Absolutely. Otherwise, we're in an aristocracy rather than a democracy, but I would hope that we'd be in a scientifically informed democracy. That's the hard thing.

DR. HAAS: The broad model you sketch out is relatively familiar to me in the sense that my training as an economist gets me into the abstract world of philosophers on many occasions. A point that Larry made a little bit earlier is one I think that's really important here in the sense of trying to get the big picture, as you stated. I would suggest certainly in this area it's not the big picture, it's the big pictures. They're different in this group, the population at large or groups of individuals who have chronic blood needs.

MR. MORENO: Right.

DR. HAAS: And that, again, creates another one of the trade-offs that you're talking about.

MR. MORENO: Right. Agreed.

DR. BIANCO: Ron first.

DR. GILCHER: In a sense, this is--one could relate it to the two basic biologic drives, that is, self-preservation and species preservation. And I take that then to individual rights versus society's rights. And that's the balance that we have here and have to determine which is the right approach.

If I as an individual am going to be transfused, I want zero risk. On the other hand, we know that we can't attain zero risk. So we have this very fine balance.

MR. MORENO: Right. Moreover, of course, we're aware of the individual who's going to be transfused. We're not aware of the individual who doesn't have access to any blood because of the protective measures that have been used to make sure that individual who's going to be transfused is not at risk. So it's also important to keep in mind the statistical victim as well as the concrete recipient.

DR. GILCHER: What I might say is that statistics don't apply to a single event. It's either/or.

MR. MORENO: Right.

DR. GILCHER: We can only apply statistics to the total number.

MR. MORENO: Right. But I'm simply saying that it's a standard allocation problem. The psychology of resource allocation is such that we're aware of the person who is in need now and doesn't get it. We're not aware of those who down the line will not get something or are put at risk because of a decision we make now about a concrete individual. It's hard for us psychologically to get our heads around them.

DR. BRECHER: Celso?

DR. BIANCO: Just to emphasize one point about the precautionary principle that maybe you could have emphasized a little bit more. There is a balance between what we apply and the results of that that we often forget as we are driven towards zero risk.

Second, I think that our role as experts is confused by the question of trust that you raised, too. We have been trying to regain trust for the last 20 years, and that is the struggle. And I think that the tipping of the balance towards the zero risk is very much the result of that.

MR. MORENO: I agree.

DR. BRECHER: Larry?

MR. ALLEN: That's essentially what I was going to say, that we're dealing with two issues here: risk versus trust. And if I accept the risk of a procedure or a transfusion, then I also must trust you and the information that you're giving me prior to make taking that risk. And, historically, not just with a community like say, for example, the hemophilia community, but minority communities, that trust is not there. It essentially has never been there.

MR. MORENO: Right.

MR. ALLEN: So there's a balance that is probably impossible to meet or match. But it's still there, and it's something that we have to be aware of and accept.

MR. MORENO: I agree.

DR. BRECHER: All right. Thank you, Jon. I think we have to wrap this up.

MR. MORENO: Thank you.

DR. BRECHER: This was a good discussion, and I think your talk was right on the money as to what this committee needs to think about.

We are fortunate that Dr. Slater is here now, and she's going to be talking about the committee charter.

DR. SLATER: Good morning. I'm happy to be here. I have two minor comments other than to urge you on on this fascinating and very ambitious agenda. I will try and stay a little bit this morning. My schedule is obviously crazy, so I will not be able to join any of the discussions tomorrow, which is very regrettable, but I think through dialog with Captain McMurtry and others from HHS, I will be amply educated on the conversations from today and tomorrow.

Again, just to thank you on behalf of the Secretary for your time, your service. It's even more exemplary today given the extreme weather conditions that we have here in Washington, but again, the Secretary is very grateful to the time that you give to our government and your expertise, and we very much try and value and process your recommendations and very much respect them.

The main change from my office this year I think has to do with the input that we did provide to the revision of the charter. You all have a copy of that charter.

The revisions to the charter were routine in that, as you know, the charter of this Committee is reauthorized on a 24-month basis, so the timing of the revisions were perfectly in keeping with that, but upon my taking this office, I noted immediately that the charter needed to be altered a bit in keeping with some of the charters that we hold for some of the vaccine committees, where members of the Committee, by necessity because of their expertise, are also members of the industry that is being commented upon. And so it's very important to make sure that the charter reflects that sensitivity and that allows you then the avoidance of the appearance of conflict of interest, and really, it's the appearance of conflict of interest that is of concern.

In this, obviously, we want to avoid real conflict of interest. That was not at issue here. It's simply to protect you in the legal terminology that conforms to these charters. Any of the other wording of the charter, I'm not going to be able to perhaps respond to. Those are the lawyers who do their job very elegantly and well, and so you have all had the charter to read.

As you know, the October 9 charter now codifies the balance that we have on this Committee of consumer, academic and industry representatives. The designated industry members, as you've read, will represent the AABB, one of the two major distributors of blood, on a rotating basis, a company that produces nucleic acid tests, a company that produces local reduction processes, major hospital organization that purchases blood and blood products, and a plasma protein therapeutic association.

As was the case in the previous charter, the 18 public and industry members are voting members. The 6 Federal ex officio members continue to be nonvoting members, and the charter designates, as with industry, the specific Federal agencies and offices that are represented ex officio. Those to repeat are my office , Public Health and Science, FDA, CDC, NIH, CMS and Department of Defense.

The Charter makes the term in membership three years for most but not all of you. As it turns out, if we're in an effort to create a rotating committee, which obviously makes sense, so that we don't completely refresh the expertise all at the same moment, and so you will be put on a rotating basis. The rotating basis is done randomly, arbitrarily. It will have nothing to do with whether you have been considered an active member, an inactive member, a good member, bad member, anything like that, but obviously we do have to put a rotation I place so that there's continuity of expertise.

So there will be some change actually in the membership, and there will be some change in the tenure based upon the reauthorization. We thank those of you who will be leaving perhaps sooner than you expected. We thank you very deeply. This has absolutely nothing whatsoever to do with the excellence of your service and comments. It's just the way government FACA committees pretty much have to operate.

The charter is--that's pretty much all I needed to say about the charter. Are there any explicit questions about that before I just go on to some of the science issues? Clear, straightforward, transparent?

DR. BRECHER: Actually, we did not distribute a copy of the charter in the package, but we'll have it for you after lunch.

MR. ALLEN: You mentioned changes. Are the members aware of these changes?

DR. SLATER: Haven't been.

MR. ALLEN: When will we be made aware of them?

DR. SLATER: I don't know. Mac, do you know?

CAPTAIN McMURTRY: Not until I get word cm Committee management downstairs.

DR. SLATER: It's a government process, so there's going to be a delay.

MR. HEALEY: Thank you, Dr. Slater. I know we have talked about this issue before, and you entered a list of government ex officio members. You mentioned CMS. Is there any sense of when we will have representation on the Committee from CMS?

DR. SLATER: Yes. We talked about that earlier. They're not here today even in an informal capacity? No. Okay. They'll be coming as soon as we can get them--informal or formal, depending on how the paperwork proceeds.

Okay. Science, you have a very exciting agenda these two days. This is really a very science-heavy meeting. We will be asking for your counsel and advice on a particular issue that we in the Department are working out right now. As you know, we are trying, based upon the President's request, to develop as detailed, as comprehensive and as complete a smallpox immunization plan as we possibly can. Our colleagues at CDC, colleagues in the Office of Public Health Emergency Preparedness, colleagues at the level of the Office of the Secretary, lots of folks have been obviously burning the midnight oils in trying to develop a plan that's deserving of the American people and that will protect them, as you all know, and have followed in terms of the reports that have issued, describing the proposal for that plan, the execution of that plan, et cetera.

Now, the hypothetical and theoretical possibility that does derive, that has been called to my attention, I'm sure has dawned on each of you in your prospective professions, has been what if we had to accelerate and initiate a mass smallpox vaccination program? By even putting this issue on the table there is no concern, there is no immediate concern, there is no likelihood, there is no probability, there is only a remote theoretical, hypothetical possibility that we might have to immunize the American public rapidly. Obviously, that's what all of this protection is about. And so the question that then arises which has appropriately been put on the table by FDA and others is that we do need to consider what would happen in that event because of the quarantine issues regarding blood supplies and blood products, and there are obviously a number of straightforward solutions or not so straightforward solutions that will be discussed and I'm sure given your complete deliberation.

What we are simply asking is for your thoughtful educated counsel as to guide us in the choice of some of the adoption of these hypothetical, potential alternatives. What would we be doing amongst ourselves, for example, to simply increase donor pool? What about encouraging donation from already immunized, or what about donation immediately prior to immunization? I mean I don't have to belabor the various alternatives. You're fully aware of them and well aware of them. We're going to take the opportunity, because you have come to Washington on these two days. We don't have a written-in-stone plan as yet. We are working this through now. We're working closely with our colleagues at CDC to develop it. As I say, there's no urgent or imminent need, but since you are all coming to Washington these two days, we thought it would be helpful to at least put the issue on the table for you and to request your consideration and advice in terms of the various strategies that would be used to ensure adequate supplies were we to have to move quickly, rapidly, across the entire universe of the United States to immunize.

I think really that was the main scientific comment that I did wish to make. Other than that, I think it's probably best to just turn the proceedings back to Mark and to your main agenda.

Are there any questions that I can answer for you on this topic or any other?

[No response.]

DR. BRECHER: I think today when we get to the Committee discussions this afternoon, that's when we'll discuss the smallpox issue, which is a very pressing one for many blood products, particularly platelets which only have a five-day shelf life.

Well, Eve, the schedule was that you would talk and then we would break for lunch. So you're just in time for lunch.

DR. SLATER: Okay.

DR. BRECHER: So we're going to break. Why don't we reconvene at 12:40, an hour for lunch.

[Luncheon recess at 11:36 a.m.]

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

(12:46 p.m.)

DR. BRECHER: If everyone could take their seats. We're going to vary a bit from the agenda. Jim AuBuchon was detained in New Hampshire, and so when he comes, we'll work him back into the schedule, but we're going to start with Mike Busch talking about an overview of viral risk and the critical issues of NAT screening.

So, Mike, whenever you're ready.

DR. BUSCH: Thank you.

So what I was asked to do was to present kind of a review of viral risks. I think we'll hear later in the presentations the focus on parasitic bacterial risks, and also I think from Jim AuBuchon later, kind of a broader context of the cost effectiveness, broader issues in transfusion medicine beyond even infectious risks and how they all sort of balance out. So my task and organization of the presentation is to quickly just kind of give a historical summary in one slide of the dramatic impact that progressive improvement in screening has resulted in in terms of increased safety, focus on the current major viruses in terms of our understanding of why we're still seeing some transmissions and what our risk estimates are, talk about the impact of the nucleic acid testing which has been implemented over the last three to four years, emphasizing first the yield of the mini-pool screening that's currently in place, discuss the critical question we're all focused on as to whether we should be transitioning and when to individual donation screening, and then present an analysis, which is in press, of the cost effectiveness of the different nucleic acid screening options compared to serologic screenings. Then touch a little bit on several other viral pathogens that are the focus of potential nucleic acid screening, hepatitis A and parvo B19. A couple slides just about the concept of emerging pathogens and how we're continuing to discover these agents, and how we're trying to frame out the process of deciding whether donor screening is justified. And then just a couple slides at the very end--again, you'll have a presentation tomorrow by Steve Wagner focused on the pathogen reduction methods which are coming towards large-scale clinical trials and potential licensure.

I just want to present a couple slides on how the availability of these pathogen reduction methods will impact the viral testing paradigm. With these methods would we be able to delete testing? Will we not be concerned about the need to add tests as we go forward?

So this slide, which is well known to almost everybody and extensively published in review articles, including one that Mark Brecher and others just published in Lancet, an excellent review of transfusion medicine issues, summarizes the risk over time--does anyone have a pointer by chance? Oh, great. Thank you. Thanks very much.

So this slide just goes back about 2-1/2, 3 decades, looking at risk over time. This is a log scale so this is really dramatic improvement. We had peak risks of HIV in the early 1980s of up to 1 percent in very high risk cities like San Francisco, probably more 1 in a 1,000 on a national level during that transient period where the virus was spreading before donor criteria were improved in terms of excluding high risk donors, and then the implementation of testing.

For HCV, this is a pathogen that had been being transmitted by transfusions essentially since the beginning of transfusions, probably at about a 1 percent rate. We see the dramatic reduction in HCV, attributable first to the introduction of surrogate tests and then the introduction of first- and second-generation HCV antibody, and then nucleic acid testing.

For HIV we had some impact of the initial impact of the screening, and then some impact of surrogate measures, and then the introduction of antigen and then nucleic acid testing.

For HBV there's been a reduction in risk partly from reduced incidence rates over time, but also improvement in the performance of surface antigen assays, introduction of anti-core which detected the remote infected people. So really dramatic safety illustrated here. But we do still have risk for these major agents and a lot of work has gone into trying to figure out why and address test development and other issues to reduce these risks.

As I'll show you in a minute, prior to introduction of nucleic acid screening and in fact even since, the residual risk is almost all attributable to the window period, and we'll focus on that quite a bit. Concern over viral variance is important. Obviously, surveillance for unusual variants like Group O or other types of HIV or variants of hepatitis C, but the companies and the FDA are very proactive in terms of identifying variants that might be missed and improving the assays to detect these variants. They're also quite rare, particularly in this country. So some, you know, variants of HIV that may be found in Africa, the frequency of their presence here in the U.S. is so remote, that their concern for blood safety is very small. Yet the improvement in the test to detect them is important. A concern over antibody negative chronic carriers, this has been something that has come up historically for HIV and then hep C. These do exist, people who were infected and yet never seroconvert, but they're extremely rare, and again, the introduction of nucleic acid testing by definition picks up these people, so this concern is being dealt with effectively by NAT.

Testing errors is another area that again we've done a lot of work to understand the rate of errors. I don't have time to present that, but the critical point here actually is that errors account for a small fraction of risk, but the redundancy we have in place now with nucleic acid testing plus serologic testing, actually serves to essentially eliminate error-related risk because these two test really are completely independent methods of detecting infectious donors, and by virtue of that, any errors essentially cancel out, or to probability that errors would occur in both systems, allowing an infected donation to get through, we've estimated now at about 1 in a billion, so extremely rare risk due to errors.

This slide summarizes risks, and you don't need to focus on the detail here. The main point here is that prior to nucleic acid testing the risk for all the major viruses was almost all due to window period, based on the kind of modeling I'll illustrate in a few minutes. The risk, even in the absence of NAT testing, of viral variants of these atypical immunosilent carriers in test errors really is quite small, and with nucleic acid testing, you know, all these risks for the viruses for which NAT is in place to have been reduced several orders of magnitude. The relative risk actually turns out to be still the same, again, with window periods still representing the major source of risk even in the post-NAT period.

Now, in terms of sort of the science that lets us understand risks, the strategy that the REDS group and others have developed and used now globally to understand risk due to the window period donations is called the window period incidence model, and it uses a strategy very simple to calculate risk by quantifying the incidence rate, the rate of new infections in the donor pool and then understanding the dynamics of the window period, and simply by multiplying the incidence rate or the rate of new infections times the duration of the pre-seroconversion window period, one can calculate residual risk. If one knows the ability of a new test to close the window like nucleic acid testing, one can multiply the incidence rate times the window period closure that this new test accomplishes and predict the yield of adding a new test or moving from minipool to single unit NAT, and we'll be really illustrating that in the next few minutes.

One point is that we can actually formally measure incidents in repeat donors based on seroconversion rates, but we have strategies that lead us to understand the relative risk of first-time versus repeat donors, and it turns out first-time donors are about two to four fold as risky of being newly infected as are repeat donors. So we actually adjust the incidence rate quantified in repeat donors to account for the fact that 20 percent of donations are from first-time donors who have a modestly elevated risk. In terms of incidence rates the REDS Group again has quantified incidence rates very carefully over time in the large NHLBI funded data set, and you can see that the incidence for HIV and HBV have actually declined significantly over the decade. This reflects improved donor selection, donor screening. So these are the current incidence rates that are used in the calculations.

Now, the other piece of this equation is the window period, and I'm not going to spend a lot of times on the details, but I just want to sort of run you through the kind of data to just kind of give you a sense of confidence that these estimates are based on a lot of data derived from window period. And the window periods for these viruses are somewhat complicated as kind of illustrated on this slide. We talk about serial stages of viremia with the early infection period being characterized by an initial eclipse phase which is the time from exposure to when one can detect the viremia, even with the most sensitive nucleic acid test. And this is a period during which these viruses enter the body, but are then trafficking directly to sort of the target organ, be it the liver or lymph nodes, and for a period of days or weeks, these viruses replicate in the target organ and do not spread through the bloodstream, so they're not viremic. And the question here is always should we be considering this period of time following an infectious exposure before we can detect the viremia as potentially a risk period, an infectious period. And the be conservative, all of our risk estimates do assume that this eclipse phase is infectious, and we'll come back to this.

We have a period that I'll illustrate for HIV/HCV that we call pre-ramp-up viremia which is essentially that in some individuals during this eclipse phase there's intermittent blips where we detect the virus and then it disappears. And again, we're doing work to try to understand and quantify this period better. Then we enter this important phase we call ramp-up viremia, which is when the virus is really spreading very actively, growing very actively in the blood, in the body, and the viremia within the blood is increasing exponentially. And then we go through this period of pre-seroconversion either plateau or peak viremia, and then the seroconversion evolves, and I'm not going to go into this at all because we have serology in place.

So this is just a sort of summary of the HIV primary viremia dynamic, so we have what from all the work would suggest would be a day zero of an infectious exposure. For HIV, immediately after that, we observe a phenomenon that we call a blip viremic event, which almost always happens temporarily right at the time, right immediately following what we would believe to be an infectious exposure. And then there's no detectible viremia for about 10 days, and then there's this rapid ramp-up viremia, that depending on the sensitivity of the system, be it individual donation NAT or minipool NAT or antigen, will detect at various time points as the viremia concentration increases. And then the antibody tests kick in and eventually a set point of viremia is established in chronic carriers.

This is just one of these panels of plasma donors serial samples that allow us to understand all these issues. As an example, this is an HIV panel. Day zero here is the day when this individual was first detected as viremic by the minipool NAT screening that was being performed on the plasma donor collections. So this unit, you see, was completely antibody negative and antigen negative, had a low level of quantifiable viremia, and then you go into this subsequent period, pre-seroconversion, seroconversion is here, so over the next 10 days or so dramatically increasing viral load, this ramp-up phase.

Now, the other thing that this slide illustrates though is that the pre-ramp-up phenomenon, which is in this case the bleed immediately before, four days earlier, you can see was erratically detected by individual donation NAT, three out of eight replicates. Then we had about a week when there was no detectible viremia, and then here, you know, about two weeks prior to the first detectible viremia, we again see the viremia. And this is this early blip phenomenon that we believe may be infectious, that's probably the very early replication or spread of the virus following the inoculation.

And then just again to illustrate, we then can study many of these panels, and each of these lines represent different infected individuals identified through plasma donor collection programs where we have serial samples to quantify the rate of increase of virus during this early pre-seroconversion phase.

For HCV it's different in the sense that there's a period of pre-ramp-up viremia that is much more frequently observed and consists of frequent intermittent viremic blips, and I'll illustrate that. Then we have a very similar ramp-up phase, very rapid just like HIV, a less than 20 hours doubling time that is detectible either by individual or minipool or antigen assays at different time points. Unlike HIV there's a very long, about a two-month period of plateau phase viremia before the immune system kicks in. And it's for this reason that the HCV yield of NAT has been so much greater than HIV because this high titer plateau phase, long plateau phase is readily detectible by the nucleic acid test. You can see here how the serial improvements in the antibody assays have closed the antibody window, so prior to NAT, you know, the reduction in risk was really attributable to the enhancement of the antibody test.

This is one example of an HCV blip viremic phenomenon where this individual was picked up by the nucleic acid testing in the plasma industry at day zero. You can see at that point on further follow up they were in the early plateau phase with very high viral loads, you know, 10 to the 7th, 10 to the 8th per ml. This is the ramp-up phase, but what this is showing is that prior to that, or actually in this extreme example for several months there was intermittent detection of very low-level viremia, illustrated here by results from four replicate HCV nucleic acid tests using the Gen-Probe TMA assay, and you can see that even with this extremely sensitive system applied to single donation samples, there was intermittent detection with three out of four replicates positive. Then the person was negative for a week. Then erratically positive, then negative, then positive.

And in studies that we're doing now we've determined that actually there is infectivity present even during these negative periods if we infuse these units into chimpanzees.

This is just a series of these cases, again showing this intermittent pre-ramp-up viremia in six additional cases. There's almost a periodicity to it, and we don't understand the biology, but it's a phenomenon that we're assuming may be infectious from a transfusion risk perspective. This again is for HCV, this ramp-up phase that we can quantify, and we can use that slope of that ramp-up phase, use this in the subsequent work, to quantify the impact of going from minipool to individual donation NAT. By knowing the incremental improvement and sensitivity as we reduce pool size, we can use the slope of this ramp-up phase to predict how many days window period closure will be achieved, and therefore how much yield will be gained by going from minipool to single-unit NAT.

Finally, for HBV we have the same kind of seroconversion panels for HBV. We have very sensitive antigen assays which are illustrated here in orange, that can pick up infection pretty early compared to the nucleic acid test. So the nucleic acid tests are sensitive, but when applied to pools, what we've learned--let me just jump to this--in a collaborative study with FDA, we've been able to look at the differential window period closure by different improved antigen assays, both newer pending licensure antigen tests, versus currently-licensed available assays out here.

And what we've demonstrated is that the pooled sample NAT will only close the window period slightly relative to very sensitive antigen tests. What we really need in order to fully close or significantly close the HBV window is a transition to single-donation NAT, and I think you'll see data from the companies later that will illustrate how they're beginning to evaluate in clinical trials the potential addition of HBV NAT to the current programs. The current screening is focused on HIV and HCV in the whole blood sector, so we are not doing HBV NAT.

If we take that data and we say okay, what are we going to gain by going to the better surface antigen test versus pooled NAT versus single unit NAT? This just kind of summarizes the data from this large comparative study, and the newer antigen test will close the window period really about the same as the pooled NAT assays, yielding about, you know, 15 to 20 additional infectious units per year, but going to single unit NAT would close the window by a month and yield more in the range of 35 to 50 units. So this is why at least my recommendation is that HBV NAT really will not buy us a lot until we get into single unit testing.

This is the same sort of curves, but unlike the last lines you've seen, the regression lines, those were on a logarithmic scale, and this is a linear scale just to contrast the increasing viral load over time that's observed with HCV, HIV and the very slow ramp-up that exists with HBV.

And this is to lead into the discussion that I want to present right now, which is the question of how far do we need to close these windows? When is infectivity maturing within a person's blood in terms of the probability that this unit would actually transmit the infection by transfusion relative to the viral load? If we actually needed hundreds of copies of virus per ml to transmit, then minipool NAT may be sufficient and we might not need to go to single unit NAT. So the question of the relationship between infectiousness and the viral load is one that's very important in these decisions.

And toward this end a number of people have been collaborating to try to understand these questions. Probably the earliest study that directly look at this was a study led by Harvey Alter, where a chimpanzee was infected with HIV, a lab strain of HIV, and that animal was actually bled, large volumes of blood were collected from that animal and frozen away at weekly intervals, that animal, that first animal became viremic at week 5 and then seroconverted out at week 8. So there was a period of eclipse where there was--clearly the virus had entered the animal, but there was no detectible viremia. Then there was the early viremic phase. And then there was seroconversion. And what was done was volumes of this stored blood from these time points were transfused into a second chimp. And what this study showed was that the units that were collected prior to detectible viremia during the late eclipse phase did not cause infection of this second chimp, whereas once we got into the early viremics phase, that chimp eventually was infused by this blood and became infected and seroconverted. This was reassuring and suggested that this eclipse phase is not infectious and that NAT should completely close the window.

But that's been overridden by the observation of transmission cases, and these are the cases that have been publicly disclosed over the last year or so, where there were transmissions due to minipool NAT negative units. This is one example, the first case observed, a transfusion in Texas that the donor was negative on this donation, and seroconverted on the subsequent donation. The transfusion of the blood from this pre-seroconversion unit, which had been screened by minipool NAT, resulted in the infection of a recipient. That recipient was then followed and tested, and the plasma from this unit was available to study, so what we were able to do was to prove first that in fact this donation did infect the recipient by sequencing the virus envelope and gag regions, and you can't see it here, but this proves that there's no question that this was the source of this recipient's infection.

What we could further do was to compare the sensitivity of the different nucleic acid test system for detection of this infection, and if you just focus over here, what you can see is that when tested undiluted, if we had done single unit NAT, this sample was detectible, and as you began to dilute it out to 1 to 8, 1 to 16, 1 to 24, which are the current dilutions being used to screen the blood supply, the ability to detect this infectious unit dropped, and so this was an example of a transmission that was a consequence of the fact that the pool testing was done. Had single unit testing been done, it almost certainly would have interdicted this infectious unit.

There was a subsequent case--I'm going to skip this, but there were similar cases worked up that showed the exact same kinds of dilutional detection. So that data suggested minipool NAT is insufficient, but that individual donation NAT might have solved the problem, but there are other examples published around the world where even single donation NAT cannot interdict all infectious units. This is one example of a paper published several years ago on HCV, where transmission occurred due to NAT screened blood, and the even single donation NAT with high sensitivity methods could not detect that infectious unit.

There had been several other cases of HCV like this and also HBV. So there's clinical data out there from lookback that shows that even single unit NAT will not consistently detect. And that's consistent with data we have from chimpanzee inoculation. This is work from Fred Prince's [ph] group, where if you infect a chimp with a single viral particle, you don't typically get transmission, but if you move up to 10 viruses in the inoculum and consistently with 100 viruses, transmission occurs, evident by either transient or persistent viremia and seroconversion. So this suggests that certainly for HCV and HBV the infectious dose in the entire inoculum is probably as little as 10 viruses. And that can be spread within the entire unit by the volume of plasma. So these NAT tests which only test a fraction of a milliliter, half a milliliter typically, are just inherently unable to capture the level of viremia that's infectious.

And this has been confirmed now, as I alluded to earlier, by studies that we've just done with Harvey Alter, where we took blood from these negative phases in these plasma donor panels and infused 50 milliliters of plasma from actually multiple donors into chimps, and we, surprisingly in the initial experiment, found that transmission did occur, even with plasma that was completely negative by replicate individual donation NAT from these plasma donors during these time periods prior to or between this blip viremia.

So this data really confirms that even individual donation NAT will not completely eliminate risk.

So where do we stand in terms of what we think the risk is? To get at that we actually, and the REDS group have modeled back the duration of theoretical infectious viremia based on the ramp-up phase doubling time data and assuming that as few as one viral copy within 20 milliliters of plasma, which is the usual volume of plasma, for example, in a red cell unit, that that could transmit. So for each virus, we've estimated the time from having one copy per ml in the plasma, to reaching the levels of viremia that are detected by current screening methods, either the NAT methods or the antigen assays. And in so doing, for each virus we could calculate out the length of this theoretical infectious window period, and you can see for HIV it's about 9 days, for HCV 7. For HBV it's longer, it's about 45 days, and as I indicated, that could be reduced dramatically by individual donation NAT.

So we have these estimates now for the theoretical infectious window period with confidence intervals that can then be combined with the incidence rates to estimate these residual risks. So these are the numbers that we're now estimating in terms of the risk of blood transmitting HIV, or HCV, or HBV, that would have screened, where the blood would have been screened by current either NAT or surface antigen assays.

So we're looking at risks, as you can see, of HIV and HCV of about 1 in 2 million, and for HBV risks in the range of 1 in 100 to 1 in 150,000.

So what would be the benefit the of transitioning further to going to individual donation NAT? If we use these same model approaches, we'd estimate that the risk would be reduced from about 1 in 2 million to about 1 in 3 million for HIV, from about 1 in 1.6 to 1 in 2.3 million. So only modest reduction in risk will be achieved by going onto ID NAT because there's this earlier phase that even the individual donation NAT cannot consistently detect, this eclipse phase.

Next I just want to summarize for you the first three years of experience with the nucleic acid testing, predominantly applied by minipools. For HCV, over the three years in a compilation of all the national screening programs, we picked up 145 viremic antibody negative units in screening 37 million donations. So that's a yield of HCV of about 1 in 260,000 unit, which is very consistent with our predictions based on the models.

For HIV the yield is 10 infected units that were missed by serologic methods in a similar denominator of about 37 million, so this is about 1 in 3.7 million donations detected by HIV NAT that were missed serologically. We can actually use this NAT yield as a tool to understand better or corroborate our estimates of residual risk--and I'll just illustrate that here--knowing the rate at which we're picking up donors in this viremic plateau phase for HCV, we can actually adjust the observed yield of minipool NAT by the relative lengths of these earlier window periods to project the risk or project the yield of going to individual NAT.

So we can take the yield of minipool NAT and essentially multiply it by the 10 over 60 which is the relative length of the pre-ramp-up to the detectible phase. And using that tool, I'm not going to go into it in any detail, but we can use this alternate strategy to estimate residual risk and these numbers here are almost identical to the numbers I just presented based on this window period model, so we feel very good now that we've corroborated these modeled risks with actually a different strategy that uses the minipool NAT yield experience.

That same data can actually be used to predict the yield of individual donation NAT, and we estimate that about 1 in 5 million donations will be detected by individual donation NAT that are currently missed by minipool NAT, and similar to what I showed you earlier the risk after individual donation NAT will only be reduced modestly to about 1 in 2-1/2 million units. So this is one of the critical issues that blood bankers are struggling with. Should we implement individual donation NAT? And you'll see from the companies where they stand in terms of capacity. We'll need to think about what the cost, logistic impact of doing that will be, in order to detect 1 in 5 million additional units, which would mean maybe two or three people per year, donors per year in the whole country, would be detected that are currently missed.

In that question, I think it's important to bring this into a societal perspective and look at the cost analysis of this to do so. And Jim AuBuchon may present this similar work. This is work that Jim's group, in collaboration with Sue Stramer and myself have recently compiled, and it's in press. But as you think about the benefit of interdicting these infectious units from a sort of cost economic perspective, you translate the prevention into quality adjusted life years that were avoided, or the loss of quality adjusted life years.

And one thing that's I think very important, and has been ignored or not recognized, is that these different viruses have dramatically different impact on people's health. HIV, for every HIV infection by blood transfusion, Jim's analysis would suggest that one causes a loss of seven quality adjusted life years. This is maybe less than you would have imagined because as you know most people who get transfused are older people, they're sick, so their underlying life expectancy is quite low, so an HIV transmission, which of course is devastating, and universally causes persistent infection and high rates of mortality and morbidity in medical care, only translates into seven quality life years.

But what I want to particularly emphasize is that HCV in a very similar compilation, is one-tenth as important as HIV in terms of the clinical consequences for the patient, and HBV is still almost an order of magnitude less important, because most people who are exposed to HBV resolve the infection, asymptomatic resolve it, and there's no clinical consequence. It's only a rare person who gets HBV as an adult who becomes a chronic carrier and evidences disease.

So the point here is that the impact of different viruses is dramatically different. And as we look at other agents, like hepatitis A or some of the more benign agents, you know, we need to constantly I think frame out the impact medically of not only the quantitative risk but the significance. If you then run these numbers through and you say, okay, what would minipool NAT do? It will pick up about--it's picking up about four cases of HIV, about 50 HCV per year, and would pick up about 9 HBV, and that can then be calculated how many quality life years would be gained by introducing that, and minipool NAT would predict to yield a 62, a total of 62 quality life years. Going to individual NAT is predicted to give us slightly better yields, slightly more quality, is a total of 90.

And then you run that into the costs of doing these different procedures so you can see that these NAT assays are not inexpensive. The minipool systems currently are estimated to cost about 15 bucks per donation when applied in the minipool context. Single unit NAT can be, you know, the companies could speak to this, but our anticipation is that having to test each unit separately will probably double the cost of doing the NAT screening to $30 per unit. We predict in our analysis that adding HBV to the current systems would add 5 dollars. And then we roll this into Jim's models, and we then come away with the costs of doing these different procedures.

And these are the critical ones in sort of gold here. The current system minipool NAT, after elimination of p24, is estimated to cost about $4 million per quality life year gained. Single unit NAT would cost about 7.3 per quality. Importantly, if you just ask what's the incremental benefit of going from minipool to single unit, that turns out to be about $15 million per quality to transition to single unit NAT. So from a societal perspective, just to lay it out there as the experts, this is extreme resource allocation for the level of gain to society. And our problem is kind of illustrated here. Our problem is the result of our own success. What this slide is showing is, as we move for HIV from no testing to the first generation assay, we dramatically reduced the risk and gained an enormous benefit in terms of quality saved. Over 90,000 quality adjusted life years were gained by simply starting to screen for antibody.

As we've moved to improve generation assays and the incidence has dropped, the incremental gain by going to next generation tests is dramatically reduced. So now as we're looking from minipool to single unit, we're only going to gain 20 qualities. So the fact is, as risk has been dropped so low, the gain of further improvement is very small in terms of yield, and the costs of these new technologies are very high.

So just a few minutes on other agents. You know, there's a lot of other virus concerns. These so-called hepatitis viruses which were discovered a few years ago, but at this point are not established to be pathogenic at all. Some of these viruses are very common in our donors. 3 to 5 percent of donors are infected with several of these viruses. Concern over other variants. Other viruses that are the focus of attention or HAV, B19, HHV-8, and as Mary will talk about in detail, West Nile virus, and then you'll hear later about these other agents.

Just a little bit. Parvo B19 is the focus of a lot of blood screening attention now. It has been transmitted, you know, very rarely by blood transfusions, but I think it's so rare that no one is considering the need to screen the blood supply for parvo B19 for purposes of individual transfusion recipients. The concern here is the plasma derivatives. The pooled plasma derivatives have transmitted parvo B19 because this virus is very resistant to inactivation procedures. And as a result, the plasma industry has implemented parvo B19 screening, and is suggesting or requesting, and FDA is participating in this dialog, that the blood collection programs also implement parvo B19 screening.

This is a challenging virus because it's a transient viremia like West Nile, but it reaches extraordinarily high titers of viremia. And that leads to this transient, very early high titer viremia, which if present in a donor unit, that then is pooled with large numbers of other donor units in preparing plasma pools for derivative manufacture, a high viremic donation can contaminate a whole pool and result in derivative contamination. So it's for this reason that the screening that's being proposed is actually designed to detect this early, very high titer viremic donation.

Hepatitis A is in this frame of the same discussion because there have been hepatitis A outbreaks from plasma derivatives. Again, very, very rare transfusion transmission cases. Generally, this is thought to have a very rapid transient viremia that's cleared within weeks due to the IgM response in the absence of a chronic carrier state. Although there is recent data from the CDC that suggests that in some people there may be persistent viremia extending out for as long as several months following acute infection.

So the issue with B19 and hep A is again how do the blood programs implement screening for the high titer viremia? One is, do we need to do it? And if we do it, how do we implement it to only detect the high titer viremic units and in a way that is rational and cost effective?

Toward that end Sue Stramer has done a study where she's done large--and this has been examined in other countries as well--where she's done large numbers of tests of unlinked donor samples to look for either the high titer viremia only detected by a dilutiona PCR analysis or directly testing for hepatitis A or B19. And in so doing, she's found no evidence of HAV viremia, so I think many of us are sort of back pedaling or saying that that's not a priority. But in contrast she's finding about 1 in 12,000 donations are high titer viremic for B19 with levels of viremia in the 10 to the fifth, 10 to the ninth range, that may well be infectious.

If in contrast one tests with single sample for B19, she found a much higher rate, 1 in 500 with full sensitivity testing. So this is a problem where we know that if we test these units undiluted, we'll actually find a very high frequency of B19 infection.

So right now, kind of in conclusion on this, is that this is leading to two options. One is an in-process model, where we would delay testing of product so that we would not interdict individual cellular blood components by B19 NAT testing, versus trying to transition to an actual real time testing for these viruses, and this is an area that is again a major focus, but probably beyond the scope of discussion of this group.

The final thing I want to mention is that these new viruses are being discovered very rapidly and very frequently with newer technologies. As the technology for virus discovery has improved with new molecular techniques, there's kind of a new virus every year that is being studied, and as these are studied, we need to quickly try to define, answer the questions of how frequently are they present in donors? Are they transmitted by blood transfusion? Are they clinically relevant? And also then ask how could we screen and what would the kind of cost benefit picture be?

And as we do that for these various agents, you know, which we do, we can try to understand, do these infections establish persistent viremia? What's the prevalence in the blood donor population? Are they transmitted? Are they pathogenic and how can we screen? And this is the kind of process that we go through as each of these new viruses is discovered.

And finally, just two slides on pathogen reduction. You'll hear a lot about that. Clearly, you know, with all this chasing all these viruses with all these tests, it seems like the obvious answer is to inactivate, and you'll see tomorrow the data both that suggests that these pathogen reduction methods are pretty effective. They have some down sides. That balance needs to be considered. But what I want to allude to is simply the question of what will happen if and when we do bring these pathogen reduction methods up. Can we stop testing? And I think in sort of compiling all of our understanding of the levels of viremia for the different viruses, during either the window period of in chronic infection, the problem we have is that the levels of viremia that exist can be very high and can exceed the capacity of the pathogen reduction methods to kill the virus.

So as we've looked at this and thought about the different viruses and asked the question of would pathogen reduction allow us to stop doing testing? We've kind of, in this sort of example, we've kind of realized that even these methods that have 5 or 7-log kill, so they can kill, you know, 5 logs of viremia or 7. If we look at the patterns of viral load in acute HIV infection, we can see that during primary infection some people have viremia that's up in the 10 to the 8th per ml. So it would overwhelm the capacity of inactivation.

So I think I'll stop at that point with the major message being enormous success but a lot of challenges, a lot of decisions that are being addressed right now in terms of enhanced testing methods. Thank you.

DR. BRECHER: Thank you, Mike.

I think we can open this up for a few questions from the Committee members.

DR. LINDEN: Mike, it's my understanding that your entire model is assuming that the testing is done by blood centers in a fully automated fashion, automated labeling, bar coding and electronic reporting the results back to the information system, keyed into release, correct?

DR. BUSCH: Yes, absolutely.

DR. LINDEN: So I guess my concern with that is that for hospitals collecting their own blood, I think the assumptions that the air is an inconsequential factor do not necessarily apply, and I think some of these calculations would be different. I think there's a significant risk of pre-analytic error. In fact even with blood centers we know that there are mislabeled specimens because the hospitals reported different blood type than the blood center has labeled the unit which means the infectious disease test results are also incorrect. Fortunately, 99 percent of the time everything's negative so it doesn't matter. But we know that happens even more frequently at hospitals where things are not automated in the same fashion. And if there's a pre-analytic error and you have the wrong specimen your back up of NAT and antibody is not going to be helpful if you don't have the right donor in the first place.

DR. BUSCH: Well, I mean, yeah. I mean our estimates--you can frame this out two ways. The truth is, our data, if we compare the results from NAT with the results of serology and cross these over, we actually conclude that about 1 in 3,000 samples are tested wrong, and that sounds bad, and that incorporates all of the pre-analytic through analytic issues. But the probability that those errors will occur on a viremic donation, results in a very low estimate of risk, and at least in the blood programs the testing on the NAT is done on a completely independent specimen collected from and labeled from the donor. So unless both those samples were mislabeled, then if both of--if they're independent samples coming through, then the risk is the factor of the--the probability of viremia times the probability of a test error on the serology, times the probability of a test error on the NAT.

So I think the redundancy of the testing is valuable in detecting error. But you're absolutely right, both in terms of system errors are happening at rates that in some context you'd say are quite disturbing, and they are probably more frequent in the less automated hospital collection programs.

DR. LINDEN: I agree with everything you're saying. I'm not convinced that these specimens are truly independent. I think if you have mislabeling, many of them may be together, but we also have observed post analytic errors which in the blood centers setting, I agree, are almost nonexistent, but in a hospital setting where things are being done manually, the wrong results can be associated with the wrong donor, or you may physically retrieve the wrong unit for discard.

And my point is you're talking about extremely infrequent events, and I think in the scheme of things some of these other also infrequent events may though be a consideration, and I am concerned about a trend that we are observing that more hospitals are collecting blood, and they are collecting more of their own blood, because of a perceived lack of availability, and because of cost issues. We actually have two more hospitals in New York now who are collecting blood who didn't do it before. Well, that means they're probably not very proficient at it because it's a brand new activity for them. And I think a modest allocation of resources addressing this issue might also enter into this equation, you know, if one were crunching the numbers, when you talk about very large resources for very, very infrequent events being addressed.

DR. BRECHER: Celso?

DR. BIANCO: Since our theme, Mike, is priorities, and according to what we heard this morning, you are an expert. What priorities you see in viral testing? And the second, considering all the things that we have in our agenda, bacterial, parasitic, pathogen reduction, if you had one lab, one person, what would you work on first?

DR. BUSCH: It was a wonderful discussion this morning, and I do think that the deliberation process that plays out, both within this Committee and in the industry and with FDA, probably has evolved the right priorities. Right now there's no question that I think the surprising West Nile epidemic this past year, it needs to be addressed, and the nucleic acid technology, that platform, having been in place, thank goodness. And the companies resourcing, bringing up that assay, I think that appropriately the focus of everyone right now is West Nile. And that's number one.

I personally don't think there should be accelerated introduction toward transition to individual donation NAT because I don't think the yield justifies it. The residual rise will be only modestly reduced. The agent for which we'll get the greatest bang, HBV, is actually a pretty minor clinical event. So I think eventually, hopefully, with really truly automated platforms that won't stress the system, that transition will happen, hopefully without as much cost increment as I laid out because those systems will allow substantial labor savings, but trying to bring up single donation now in the large blood-testing programs, you know, the labor impact, the cost impact, to my mind is not warranted.

DR. BRECHER: Ron.

DR. GILCHER: Mike, what is the role of neutralizing antibody in preventing the transmission? When I saw the blip situation, which you showed with the human parvo virus, at the lower levels, is neutralizing antibody really effectively preventing the transmission, and if--really the question then is, if there were more neutralizing antibody per pool, could that--

DR. BUSCH: I think that's thought to be the case. Others may know better. Jay?

DR. EPSTEIN: It is thought that the low titer viremic samples that have significant antibody are noninfectious. That has not been rigorously proven. But it has led to the concern that there might be a danger in screening plasma fractionation for detecting low titer viremia because that could have the adverse effect of eliminating the majority of the antibody positive units.

One of the surprises with parvo virus, it had been thought that you develop your antibody, you clear your virus, but it's now known that many people can have a low level viremia which can persist in fact for years. So we are concerned about the interplay of antibody and virus.

DR. HOOTS: Two questions, Mike. First, in terms of quality of life years, say, it may even be more dramatic for certain viruses if you don't factor in the fact that you can vaccinate, say, against HAV and hep B, because there, since you could actually prevent most of those infections a priori at a much lower expense than doing screening, then it would even be more dramatic for those particular viruses. And that's just a comment.

DR. BUSCH: Yes.

DR. HOOTS: And then secondly, for viruses like parvo that are indigenous, where you're trying to make the difficult decision about whether to screen versus attenuate and pool products, and you have that potential of overcoming the attenuation capacity of the processing, it seems to me at the very end of the day it's going to be very difficult to prove, since it's indigenous in the population, that in fact any small incremental leftover, like if you eradicate 10 to the 6th but 10 to the 7th were there, so you have a 10 log in your pool, that that ever could be implicated as a cause of infection in a recipient.

DR. BUSCH: Yes, I agree. I mean it's kind of--again, toward the discussion this morning, blood transfusion transmission of all these agents, to be blunt, is a trivial source of infection in this country. It used to be if you go to Africa still where they don't screen the blood very well, you know, 10 percent of transmissions, and even in the U.S., prescreening, you know a substantial proportion of transmissions of these agents in the population were coming from blood transfusion. But now in the setting of the current screening, you know, for these frequent infections, the blood supply is a very, very small contributor to the overall population incidence, and yet the resource is focused on prevention of these rare residual blood transmissions. So they could have a huge impact in other aspects of public health prevention of these agents.

DR. BRECHER: Mike?

COL. FITZPATRICK: In the comparison of individual donor versus minipool, is there a way to factor in the resolution of false positive pools with minipool versus the lower incidence of false positives in individual donor, and the costs of resolving the minipools plus the cost of lost products that maybe shouldn't have been lost?

DR. BUSCH: Yes, we haven't done that. It's possible. I know I've seen some presentations in the military work by Gen-Probe that have tried to factor in, because you folks have implemented single unit. I mean the rate of false positive coming out of pool testing has actually proven to be quite low. And it's all attributable to contamination. There's no biologic false positivity going on, so it's down in the range of 1 in 30,000 donations that resolve out, but the frequency that minipools are false positive and need to be further tested to figure out individual units, I forget that exact number.

It's a good point though. There will be some offset of cost related to the loss of--the discontinuation of the pooling, the discontinuation of the logistics and the workup of the reactive pools. So maybe that's a good point. We need to incorporate a cost differential, and we have not done that.

DR. PENNER: Mike, do you see in the future some possibilities of stratifying the blood products so that immune suppressed patients would be like we used to do for CMV, would receive that blood product that had been tested for all of the agents as opposed to the rest, so we don't exclude a lot of donors?

DR. BUSCH: Yes. I think that from a rational sense, yes, it makes great sense. There's subset of patients that are at risk for significant disease, and they're the same subset for almost all these other viruses. In addition there's concepts of geographic screening. For West Nile you could focus particular areas, obviously chagas disease. You get much greater yield focusing on particular geographic regions or even demographics of donors. But the reality is, when you get into the big systems, the Red Cross's that are highly regulated and centralized, the logistics, they just conclude that they don't think that's possible, that they can't bring up selective testing of a subset of donations, selected inventory management.

So, you know, when you get to the people who are running the programs they all say, it's all or none. And I agree with you that this should be something that we should overcome and we should think about establishing capacity within the systems for selective testing.

DR. PENNER: So you don't think you can provide the bins for those with the lemon flavored and those with strawberry flavored and so on, that we'd withdraw from nationally?

DR. BUSCH: Theoretically it can be done, but there's two issues. One is the logistics of actually doing it and properly managing, testing of a subset of units, managing that inventory. The other becomes the transfusion policy side of it. Who really deserves that safer blood? You want to pay the extra $10 for your child to get that extra safe blood, and yet you're told your child can't have it because he doesn't have leukemia? These are the ethical side of this that need to be also considered.

DR. BRECHER: Thank you, Mike. That was very good.

We're going to continue to juggle our agenda a bit, in that we're going to move the discussion of West Nile virus up into the next slot. So Mary's going to be talking about West Nile virus.

DR. CHAMBERLAND: Thank you very much.

Well, the story with West Nile virus transfusion transmission really began in August of this past year when it became known that four individual solid organ recipients who received their organs from a single organ donor became infected with West Nile virus. And one of these infections in one of these recipients ultimately proved to be fatal. The ensuing investigation determined that this organ donor, over the course of about a two-day period had received blood components from some 63 unique donors. It was possible to go back and retrieve specimens for testing, and it was determined from a blood specimen that was obtained prior to transfusion, that the organ donor tested negative for West Nile virus by PCR as well as IgM testing.

However, testing a sample that was retrieved immediately before organ harvesting, now demonstrated that over the course of those two days the donor now tested by PCR and actually we were subsequently able to isolate the virus.

Although we can never rule out with 100 percent certainty that this organ donor acquired infection from natural mosquito transmission, I think quickly for many of us a working hypothesis began to develop, that perhaps the donor had acquired infection from one of the many transfusions that were received.

Well, sure enough, shortly thereafter, CDC began to receive reports of other possible cases of transfusion associated West Nile virus infections. These infections increased rapidly during the month of September, peaked in October, and then sharply declined during the month of November.

Once a case report was received a number of activities were initiated to investigate, including determining the number and type of component that had been transfused into this recipient in the four weeks before illness onset. Efforts were made to retrieve what we termed initial donation samples, namely, retention segments, untransfused components such as plasma units, or residuals from nucleic acid testing tubes. The samples were then tested for West Nile virus RNA by TagMan rtPCR, and for IgM antibody by ELISA. Efforts were also made to obtain follow up questionnaire and serum samples that could be tested for West Nile IgM antibody from donors who had donated components that were received by the index recipient. And then in instances in which we were able to find that donors did appear to have evidence of West Nile virus infection at the time of donation, efforts were sought to find the co-component recipients, namely, other recipients who had received components from the same donation.

Through January 3rd, when these slides were last updated, CDC had received some 57 possible cases that had been reported dating back to August 28. 19 of these cases were ultimately determined not to be transfusion associated. 8 persons did not actually, on further follow up have evidence of West Nile virus infection; 3 had received their transfusions after their symptom onset; 2 individuals had symptom onset 28 days past transfusion; and then 6 individual recipients did have West Nile virus infection, but on follow up we were able to determine that all donors were negative for West Nile by IgM testing. Some 24 remain under investigation.

Actually in terms of late breaking updates, we're actually at a point now where we have 17 confirmed cases of transfusion associated transmission. What's happened is that some of these 24 that were under investigation have shifted around as a result of laboratory testing of things like retrieved components. That still is in process. So this is still a bit of a story, an evolution for this past season, although I think it unlikely that we're going to uncover many more cases.

Well, a few slides now about the cases. First, a case definition. Our working case definition--and we're somewhat still refining this, but at this point in time a case of what we're calling a confirmed case of transfusion associated West Nile virus infection involved a number of requirements. The first was finding an implicated donor. An implicated donor was defined as a donor who had initial donation samples which tested either PCR positive or equivocal, in combination with either actually isolating virus from a sample or documenting subsequent seroconversion, namely the donor developing IgM antibody on follow up.

Index recipients were defined as individuals who had probable or confirmed West Nile virus illness within four weeks of transfusion from an implicated donor. Once we could link an implicated donor to an index recipient, as I said previously, efforts were made to notify and follow up co-component recipients, and in these instances, we've been able to identify co-component recipients who tested IgM antibody positive, some of whom did and some of whom did not appear to have viral symptoms.

Our 14 confirmed cases--and as we go along I do have some information about the three newer ones the I can add on in sort of an ad hoc basis. But for the 14 that were reported through the 3rd, 57 percent were female. They ranged in age between 7 and 75 years with a median of 40 years. The confirmed cases resided in some 9 different states, and I think it doesn't take a little bit of imagination to see that the distribution of these cases roughly paralleled the human epidemic that we saw this past season.

Well, I think we have finally reached the point where we're not going to be able to line-list, if you will, all of our individual confirmed cases on a single slide, but let me give a few summary comments here. First of all, you'll note on this slide there's four and with the three new cases we now have six instances in which we have more than one recipient that can be linked back to a single donor. So these patients that are bracketed, if you will, link back to a single donor.

The underlying conditions for these patients included two who were post partum, one individual who had received a liver transplant, and it was determined that the organ donor was negative as well as another solid organ recipient from that donation. We had five persons who had hematologic malignancies, four of whom had bone marrow transplants. We have three other individuals with cancer, other types of cancers, four persons with surgery or another medical condition. All of these were individuals that were older than 70 years of age, and one whose diagnosis is pending. So I've supplemented a little bit with what's on the slide with our three new cases.

As you might imagine, mosquito exposure was difficult to ascertain with certainty in most situations. All of these patients really resided in areas where there was ongoing human activity. However, in some instances we were able to determine with pretty good certainty that mosquito exposure either was not at all possible, for example, patient four, who had been in respiratory isolation for 65 consecutive days in a hospital prior to onset of symptoms, we felt that there were not really opportunities likely for mosquito exposure. And then at least three other individuals whose underlying medical conditions really precluded a lot of opportunities for them to be going outdoors.

Most of the patients developed West Nile meningoencephalitis, the most severe manifestation of West Nile virus infection, and in fact, 4 of these 14 had fatal outcomes to their infection.

The next two slides kind of walk you through, if you will, sort of in a very compressed time frame, what we spent, and many of you sitting in the room, spent your entire summer doing it seemed. Kind of walk you through the major epidemiologics and laboratory milestones as these investigations unfolded.

In this particular situation we're going to start with Patient 5, one of the patients who had an underlying solid cancer. This individual, because of the underlying diagnosis really had had a kind of--sort of a poor clinical situation to start with and had been intermittently hospitalized related to complications from the cancer. Illness, however, seemed to evolve over time. Mental status changes started appearing, and beginning at the end of September, serum was drawn for West Nile virus testing among other things. Mental status symptoms progressed to include seizures and optumdation [ph], and an LP was done on October 2nd. Several days after these tests were drawn, results became available and it was determined that this individual tested positive for West Nile virus by IgM testing of CSF as well as serum.

The hospital was able to go back, retrieve a specimen that was still available, and determined that actually five days before this interesting phenomena, the individual testing IgM negative but PCR equivocal.

Well, a lookback was done. It was determined that on the 18th of September this individual had received four units of packed cells. Fortunately, all four retention segments were available from those packed cells. They were tested, and one of the four was found to be positive for West Nile virus by PCR TagMan. Follow-up interview and testing of this donor elicited a history of some five days prior to donation of the onset of fever, headache and eye pain. The donor apparently felt well enough to donate on the 23rd, but interestingly, after the donation, illness evolved to include a rash on the 27th of August. Follow-up testing which was done in October found that this donor was IgM positive, and I should add that the retention segment, although PCR positive was IgM negative, so a seroconverting donor.

The blood collection agency, as part of their efforts to determine what happened to the co-components learned that the plasma had been transfused to a second patient, Patient 6.

This individual had had a number of blood products transfused over the previous 30 days, but the FFP from this implicated donor had been transfused on the 6th of October. Two days later onset of fever, which ultimately progressed to include a rather severe case of meningoencephalitis.

A fair number of specimens could be retrieved from the hospital to test, and we actually see kind of a nice evolution of some of the markers for West Nile. Prior to transfusion of the implicated unit, serum was negative by IgM and PCR testing. Some 10 days later, PCR now positive, IgM negative. And then very interestingly, as far out as October 21st, which is some 15 days after transfusion, this individual, also a cancer patient with immuno compromise, still testing PCR positive, and now the IgM has come up.

So this type of a scenario, this type of an evolving investigation is something that played out on a regular basis unfortunately this summer.

Well, the next few slides kind of pull together all the data that we've learned from these confirmed cases. This slide summarizes information then about the recipients. Their illness onset occurred between August 1st and October 23rd.

For three individuals, however, it was not possible to actually distinguish an onset date for viral illness. These were the individuals who were notified as part of the co-component investigation and follow up, and although testing IgM positive, because of their very complicated underlying medical conditions, review of medical records was not able to really tease out a significant date that we can say this is when fever began or whatever. For our three new cases this information is still pending.

The interval from transfusion to illness onset for these 11 individuals ranged from four to 23 days with a median of 11 days. And at least as far as we've been able to measure with these case reports, the duration of PCR positivity after illness onset persisted, for at least one individual, for 17 days. And then finally all types of blood components were implicated.

The 10--or actually for the 11 donors, days of donations fell within this interval of July 22nd through September 20th. In looking at donor illness, some really kind of maybe surprising findings, not what we might have expected. Usually in the course of West Nile virus infection, the vast majority of infections are asymptomatic. About 80 percent of individuals, when infected with the virus, will have no symptom onset. However, we actually kind of saw the reverse of that in our implicated donors, namely that most of them ended up being symptomatic. For two of these individuals their symptom onset was predonation. One donor had some one to two week history of URI type symptoms prior to donation. Another donor had symptoms beginning five days before donation. Six donors had their onset of illness after donation, four of these clustering within the first five days. Again, interestingly, for a couple of donors, onset of illness was somewhat far removed from donation date, as far out as 11 to 21 days. Our newest donor here was also asymptomatic, so now incorporating the new cases, we have three asymptomatic donors.

And then this just looks at the maximum intervals from donation to transfusion by product type and the farthest interval that we've been able to document was FFP that was transfused 44 days after collection.

This slide looks at the timing of the each implicated donor's donation in relationship to human West Nile virus activity in the counties where the donors resided. So if you look at, this is the date, for example, for implicated donor no. A residing in County A. This is when cases first started to occur in that county, and before this individual donated, there had been two previously reported human cases, and that was a period of 25 days prior to this individual's date of donation.

So kind of the take home message from this is that while many of the donors donated really at the peak of human activity that was occurring in their county, we have instances in which for at least a couple of these donors, they clearly were at the leading edge, if you will, of cases that were ultimately reported from their county.

I think this might have some implications, if again, in trying to plan for the upcoming season, depending on availability of a screening assay, if we find ourselves in a situation where we're going to be relying on national surveillance and reporting data as an indicator of when perhaps, let's say if we had limited assays available to use, if we're going to rely on surveillance data to indicate now is the time to start testing or this is the place to start testing, it's not going to be 100 percent effective. I mean that shouldn't be a surprise to people. But this was just kind of an interesting way to document that.

I have one slide here about some of our experiences with PCR testing. Until the transfusion investigations came long it had really never been envisioned that TagMan PCR was going to be used on samples such as the retention tubing segments, and as many of you know, the segments are really less than ideal specimens to test. Many of them were composed largely of red cells and not whole blood. They were diluted. They were anticoagulated. They were leukoreduced. They were hemolyzed. And they were subject really uncertain temperature controls. So they're not what you consider an optimal specimen, really even for serology testing.

This slide looks at the correlation of PCR testing of the initial donation samples with the follow up serology testing for all donors, not just the implicated donors, and it stratifies it by what we call--what I'll call less ideal or less optimal sample type, namely the retention segment, and then the ones that we think are higher quality such as retrieved FFP or residual from a nucleic acid testing tube.

For 6 of the 8 individuals whose retention segment tested PCR positive, indeed they were found to be IgM antibody on follow up. We have 2 donors, however, whose retention segment repeatedly tested PCR positive, but they did not develop evidence of IgM antibody, so our working hypothesis is that this PCR positive test on the retention segment was in all probability a false positive.

In this situation we have 2 of 3 individuals whose segment tested PCR negative who were positive by IgM antibody on follow up. Now fortunately we were also able to test, along with the segment, a retrieved untransfused unit of FFP, which tested PCR positive. So this kind of verifies what we thought was going to happen for sure, is that we might have false negatives because of the poor quality of the specimen.

Looking at the better quality specimens, if you will, the components that were retrieved in the nucleic acid tubes that we were able to test, kind of a--4 of the 6 donors who tested PCR positive, indeed had antibody on follow up. Kind of a curious situation here where 2 tested negative on follow up, and when CDC went back in their lab and retested this initial donation sample and sent it out to a second laboratory, the second go arounds were all PCR negative, so for at least unclear reasons to me there was at least initial PCR positivity that was read out.

Well, to sum up, I think the efforts here of so many people have really left us feeling fairly confident that we have good evidence for transfusion transmission of West Nile virus. 10 of 10 and now 11 of 11 implicated donors had a PCR positive initial donation sample. In one instance we were actually able to isolate virus from a unit of FFP that had not been transfused. All 11 donors subsequently seroconverted after donation. And then we had at least 8 of 10 donors who had viral symptoms either before or after donation.

Also further bolstering our evidence here we have at least four situations in which recipients were rather unlikely to have had opportunities for exposure via the more likely mosquito acquisition. We have now six instances in which multiple recipients were associated with a single implicated donor, and there seems to be compatible timing between transfusion, viremia and symptom onset in recipients.

Well, while all of our hard work provided us with some information, I think all of us would agree that it has left us with more questions than answers, only of which a small number here are highlighted.

It's clear that we have to have a better handle and definition of the clinical course of West Nile Virus infection and viremia in individuals. We certainly want to better define the scope and magnitude of transfusion transmission, and this can be approached in several different ways, including looking at viremia prevalence survey in donors, looking at the rate of transmission from viremic donors and what the associated risk factors for transmission might be, also looking at seroprevalence in frequently transfused populations.

Now, over the ensuing weeks and months, I think we actually are going to be having additional data available to help us get a handle on some of these issues. For example, to date, there has been a small number of donors that were tested for evidence of viremia. We've tested about 1,500 donors from three different locations, and, retrospectively, we've appreciated these probably were not optimal, in terms of coming at a time or a place that was experiencing high human activity. All of those were negative.

However, in the upcoming weeks, we hope to test several thousand specimens that the Red Cross and Susan Stramer is going to be sending to CDC for testing that are going to be coming from areas of the country and at periods of time where there were high levels of human activity.

Seroprevalence in frequently-transfused persons. As many of you know, CDC has, for several years, our Hematologic Diseases Group, Bruce Everett and his group, have initiated what's called the universal--I'm blanking--but their surveillance system in persons with hemophilia that involves collection of blood samples. They are going to go back and retrospectively test these samples.

They, in the last fiscal year, were also able to add on importantly a new population; namely, persons with thalassemia, and it's hoped that we'll also be able to initiate protocols for testing of these samples.

One way to try and approach rate of transmission or get an idea of that risk is through mathematical modeling, and I'm going to close on my last couple of slides here. I think many of you are familiar with Lyle Petersen and Brad Biggerstaff at CDC published a model a couple of years ago looking at what the experience was in New York City in 1999, when West Nile made its initial introduction, at that time, into the U.S.

They updated their model, and it's interesting that while overall in the United States the maximum risk for the past season was felt to be about 1 per 10,000 donations, this risk really varied in areas of the country. So places like Cleveland, Detroit, Chicago, where we knew there was a lot of human activity, that risk approached something like 15 per 10,000 donations.

What also became apparent in their modeling exercise is that this risk was not only focused geographically, so the whole U.S. is down here, but it was also really tightly focused in time. So really this is the beginning of August, and this is kind of mid-September. So over a 4- to 6-week period is when the peak of these cases were occurring, and hence when you would expect the peak of transfusion transmission risk to have occurred from donations collected during that time period.

So I think I'll close on one final note, which is all of the data that I just summarized really represent the efforts of hundreds of investigators in health departments, blood collection agencies, hospitals, organ and transplant organizations, as well as numerous federal agencies, donors and patients around the country, for which we're very grateful.

Thank you.

DR. BRECHER: Thank you, Mary. We're going to open this to questions. I'm going to take the Chair's prerogative and ask the first question, if I could.

Mary, the epidemic originally started in the Northeast, and I noticed that now that we've investigated the transfusion-transmitted cases, there aren't any from the Northeast. They're all from the Midwest and from the South, probably, I imagine, reflecting this rolling epidemic, and so next summer where are we going to be? Is it just going to be the West that has the transfusion-transmitted cases? So that's one question, and then are we going to then go into a low level sort of like St. Louis encephalitis.

And then the second question is, of the 17 confirmed cases now, you said there were 4 deaths in 14. Were there more deaths in those three cases that were added?

DR. CHAMBERLAND: I don't have that complete information, so I can't, in regards to your last question, I'm not sure about the--

DR. BRECHER: So somewhere between four to seven deaths proven.

DR. CHAMBERLAND: I don't think it'll be seven deaths, but--

DR. BRECHER: Okay, how about the first question?

DR. CHAMBERLAND: Predicting the future, not something that I think I'm going to go out on a limb. The Northeast did not experience a large amount of human activity this year--some, but you're absolutely correct, human activity exploded in the Midwest this year.

And what the future, there's any number of scenarios that have been put out there, ranging from a lot of cases in the West, perhaps, because it's kind of relatively virgin territory, if you will, to the other extreme, which is, gee, maybe this will be like St. Louis encephalitis, a real big epidemic in 1975, I think it was, and 3,000 cases reported and then has petered out to be a phenomenon of a couple hundred cases a year, so maybe somewhere in between, but I think, at this point, and I'm sure others will comment, everybody is gearing up for I think we have to be prepared for kind of, I won't say worst-case scenarios or certainly the continuation of significant human activity.

DR. BRECHER: Thank you, Mary.

Celso?

MR. BIANCO: Mary, this was a wonderful summary. I learned a lot of things, but there are things, particularly considering I think that everybody here knows that we did a big withdrawal of frozen products for the entire period of the season with human disease in many states, which was painful to do, was difficult, created a lot of spot shortages, and I keep asking myself what benefit did we derive from it.

But there were fascinating things there that I'd like, actually, if you could comment a little bit. The tightness of the epidemic, it's so clear that it goes from a certain period in August to a certain period in September, for the entire country, despite the variability that we have in terms of temperatures and mosquito seasons, that is stretched in the South and shorter in the North.

So I wonder if, in terms of the question that Dr. Brecher asked, that is, can we make predictions, and our concern that our tests may not be ready on the date that we want, that is, the date that the first mosquito flies in, can we make rational attempts to policy, and our priorities, what would they be at that time?

So it would be very nice to see if we could correlate all of that, that is, the surveillance systems for mosquitoes, mosquito pools that are positive, birds, and see if all of that comes.

What is very interesting is that we continue having cases, I remember I think the last one in Texas was December 1st or--

DR. CHAMBERLAND: Yes, Texas and Florida have had many cases.

MR. BIANCO: --something like that of meningoencephalitis, but your last report came on October 23rd, exactly four months from today. Yes, there is probably delayed reporting, difficulty investigating, but isn't that association strange for you or is that all of the mechanics of reporting that is explaining it?

Maybe I said too much, but you'll deal with it.

DR. CHAMBERLAND: I think, in regards to your last comment here about the late cases, there have been some late cases coming out of the South. Texas, and I believe Florida had an isolated case in December, which I think reflects the sense that in Southern areas of the country there might be ongoing transmission, but apparently it's ongoing at such a low level that at least we haven't been able to detect it in terms of the transfusion. I think we all recognize that what we detected may very well have been the tip of the proverbial iceberg.

And the way I feel confident about that is when we went back and did our co-component recipient notifications, once we had an implicated donor that was a tie to that initial recipient who had illness onset and the whole works, these other co-component recipient cases would never have come to our attention because they were very sick people, they all had fevers, they had respiratory illnesses, whatever, and they hadn't even been tested for West Nile because it was impossible to distinguish out a specific viral illness in the middle of everything else that was going on.

So I think the other thing that happened is that I think we either, A, used up all of the product, so certainly the platelets and the red cells are all gone, except maybe the frozen, there's frozen red cells that were collected during peak periods of time, and then the retrieval of the FFP was supposed to be the final touch, if you will, in terms of trying to pull back any potentially infectious units that may be out there.

I think you're absolutely right that there is going to be, national surveillance and reporting is going to be a really critical factor to get an early handle on this year's season.

And I'm not a West Nile Virus expert. It's not exactly straightforward. At least my understanding, for example, is that, as people are aware, there's these sort of sentinel systems in place looking at, for example, mosquito pools, which can be helpful, but my understanding is that they are somewhat limited in their usefulness, the information is perhaps not as kind of timely as you would like, and you can only test in limited areas.

My understanding that, at least in previous years, that the cases in horses and birds have ultimately occurred in counties and occurred preceding human activity. They're still in the process of analyzing this year's surveillance data, so I don't know if that association will hold out.

At least in the Northeast, prior to this season, I am told that the indicator of dead birds was a good correlation with subsequent human activity. Whether that pans out in the less-populated areas of the Midwest and the West, don't know yet.

There is going to be, in mid February, CDC hosts an annual West Nile Surveillance Conference, a lot of the audience largely there being health departments, but other groups as well. So they are working very hard to analyze a lot of this year's surveillance data in time for that meeting. So there's more data to mine, if you will, apart from just the transfusion data.

DR. GOMPERTS: Mary, following on this, the questions, as well as your comments, from the point of view of herd immunity in birds, mammalian populations, human in different parts of the country, clearly, that's going to correlate with the expected outbreak, but are you modeling the St. Louis encephalitis outbreaks in relationship to projected expectations in relationship to West Nile Virus?

DR. CHAMBERLAND: That's a really interesting comment because I think the experience with West Nile has rekindled a lot of interest in the related flaviviruses like St. Louis and like dengue, and I think there's efforts actually underway. I'm not specifically about mathematical modeling, but certainly there have been efforts underway to retrospectively go back and see if, in some instances, there might have been transfusion transmission that would have been missed.

The situation, I think certainly with dengue, I think the sense has been out there that definitely transfusion transmission, blood-borne transmission was a real possibility. There were clues from that. There have been isolated reports in the literature of needlestick transmission of dengue and kind of a rather shaky description of potential transmission via stem-cell transplantation, but these were occurring in areas that were really endemic, where huge segments of the population are infected.

So in that kind of a situation, it was very difficult to tease out, if someone is in the hospital and got transfusion, teasing out community-acquired versus transfusion-acquired infection I think becomes very difficult.

I think we had the advantage, if you will, of the country as a whole, and certainly big parts of it being relatively naive with respect to previous exposure to West Nile, that it facilitated our ability to recognize and document these not just transfusion transmission, I mean, this was a banner year in many ways in that additional modes of transmission of West Nile were documented, including transmission probably by breast milk and in utero transmission, and there was recently also occupationally-acquired infections.

So I think we learned a lot this season about West Nile, lots more to learn, and I think with the upcoming season and people gearing up for assay development, plans are underway by others to really take this as an opportunity to really learn a lot more about this flavivirus and perhaps others.

DR. HOOTS: Just to follow up on Ed's question related to herd, do you think there's a possibility that the low prevalence of cases in the East could be a phenomenon of primary T-cell recognition that occurred in the previous season, and therefore a subset of the population actually, because mosquitoes in certainly indigenous areas are ubiquitous and people get bit all of the time, and if there were as many birds as were dying in the previous year around New York, for instance, that there was a phenomenon of herd that could help explain why they had a low attack rate?

DR. CHAMBERLAND: I think that's a possibility, but I'm not sure we have the data to support that yet, but it's an interesting possibility.

DR. BRECHER: Mark?

MR. SKINNER: I think you raised a question that maybe you didn't intend to raise, but when you referenced the UDC study that Bruce Everett is doing, given that most of us have now seen the clearance data with spiked West Nile for the products the community uses and that it's shown that it's clear, is Dr. Everett looking for something that we shouldn't assume? Is this simply confirmation or just a part of a routine study? I want to make sure there isn't a lingering question out there that he knows something we don't know.

DR. CHAMBERLAND: No, I did not intend to raise a new concern. I think the data really that others have presented in other venues really suggests that this virus is readily activated by the routine procedures that are in place.

I think there was, however, an interest in really documenting that with data, and I think, interestingly, the addition of the new population in the UDC, namely, patients with Cooley's Anemia who receive cellular components on a frequent basis, if you will, in essence I almost sort of view them as sort of the ability to have kind of a case control or exposed/unexposed population.

Persons with hemophilia, I would expect, would just represent what the general population rate of infection is. Persons with Cooley's anemia who get frequent red cell transfusions, theoretically, you might expect to be at increased risk. So this is an example, I think, of where having these repositories in place that you can test for new emerging pathogens pays off, but no one's expectation is to find an increased rate in the hemophilia population, but apparently there has been a lot of interest in documenting that is my understanding, so they want to go forward with that.

DR. BRECHER: Thank you, Mary. I think we're going to move on.

We're now going to step back to NAT viral testing, first talking about the Chiron-Gen-Probe platform. Neil Gunn will present first.

MR. GUNN: Thank you. I'd like to thank the Committee for inviting me today. I'm representing Chiron Blood Testing and also Gen-Probe, our partner in the development of NAT assays.

I think, as most of you are aware, we have developed, and introduced, and implemented a series of tests over the many years that Chiron has been involved in blood testing, and most recently we've implemented the nucleic acid testing for HIV and HCV, which was approved last year.

Building on the two previous talks, I want to talk somewhat now about the technology, about our development plans, hopefully, give you some information to address some of the questions posed in the previous two talks.

I'm not sure that we'll answer all of them by any means, but talk a little bit about individual donor testing, the technology and also about, probably a question in many people's minds, the development and the probability of development of a West Nile Virus assay in the time line which is being put out there. So, in the next few minutes, I want to try and address those issues.

As I briefly mentioned in my introduction, we have a strategic alliance which is focused very much on principally and exclusively on safer blood supply. We have an alliance with our partner, Gen-Probe in San Diego, and the principle behind this was to introduce a new nucleic acid test, TMA, which was specifically designed for high-volume throughput blood screening, and one of the attributes of it was that it allowed multiplexing, which I'll talk briefly to, which has been introduced, and also it provides some benefits in that it's a single tube assay, and so it minimizes transfer and allows pos ID the whole way through the test.

If we look back a few years, as was done earlier today, in terms of some of the milestones, obviously, in 1994 was the challenge and direction toward zero-risk blood supply, which is an aim which many of us have and I think will continue to be one, but as highlighted earlier by Mike, is something that has to be pragmatically looked at.

In 1996, Gen-Probe was awarded a contract to develop the blood-screening program by the NIH, and then two years later the alliance was formed with ourselves. I'm very pleased to say that just a year after that, wide-scale implementation under an IND of the Procleix, as it then became called, a multiplex assay for HIV and HCV was introduced.

Last year, in February of last year, the approval of the assay came through. And I'm sure, as everyone well knows by now, implementation proceeded and, consequently, the approval of the product was adopted, and widely adopted, around the U.S., and approximately 75 percent or slightly higher of the U.S. blood supply is currently being tested with the approved Chiron assay.

Last year, was a big year for milestones, if we list these out here. As we just heard, later on in the year, we had the challenge, if you will, by the FDA to develop and implement West Nile Virus assay by the early summer.

Now, when we look at the time lines, which Mike put up earlier, of some 20 years of assay development for HCV, and the reducing risk, we had a challenge in front of us which was approximately eight months because we have the target date of July to try and implement a West Nile Virus assay. We have also heard, of course, that we want to do it by the summer and the first mosquito. Well, if we look around the country, the date of that, clearly, varies significantly, and our target is to implement by the 1st of July. I'll show you later we're quite hopeful of doing that.

Certainly, as a significant help to that program, the NIH extended the contract which was previously awarded to help develop this assay. So our target for 2003 is to introduce this product, under an IND, and also some further developments which I'd like to talk to.

Briefly, what is the assay, and why do we feel some level of confidence in being able to actually develop a new assay, new nucleic acid assay in this dramatically shortened period of eight months?

Well, I apologize for some of the text here, but this is the steps of the Procleix product. The sample pipetting, it then has a capture of the target, amplification, detection and results.

I put this up at this time to really talk to some of the issues earlier around individual donor testing. Here, we have a time line of approximately five hours from the initial sampling to the ultimate result. This is a result for two markers for HIV and HCV, and this time line--this is important for the discussion--doesn't include any pooling time. Pooling can maybe take up to 45 minutes, maybe a little bit longer, an hour, dependent on the size of the pool and the algorithm used for pooling.

This is a relatively simple procedure. There are some manual steps in it which we're looking to automate, and I'll talk briefly to that later as well.

Just to remind us of the claims which were approved last year by the FDA, for the 16-pool member, we have a specificity exceeding 99.5 percent, 99.67, in the pool size which is used within the U.S., which is a pool of 16 donations.

In individual donations, specificity is slightly improved, and again, in terms of seven sensitivity, again, there's a marginal improvement for the multiplex when you move to an individual donation.

Now, just for explanation, the HIV discriminatory line there, because it's a multiplex, if we get a positive result in the pool, the algorithm is to deconvolute the pool to test the individual donations, and the one which proves to be positive, you then test with a discriminatory probe to identify whether it's an HIV-positive or an HCV-positive, and so we've got data on both individual donations and pooling donations in terms of performance, and Mike indicated earlier the level of yield cases predicted and the actual found.

He also mentioned something around the subtypes, and this was really trying to put out that we want to be able to identify these subtypes, however rare and unusual they may be. Clearly, if there's an ability to identify them and test for them, we should take on that role, and this is what was achieved, with sensitivity for HIV at 100 copies per mL for the Group M, Group N and O.

HCV subtypes listed there with only the Subtype II having a slightly higher level of sensitivity at the 300 copies per mL. So this was where we targeted, and this was achieved and approved last year.

Just briefly, again, to look at the instrumentation. As you can see, there's large automated components for both pooling and the assay, and this is again an important aspect with any move toward individual donation testing. The Tecan product is used both for pooling, and it can also be used for the assay. So in terms of instrumentation, they can be swapped and moved into different roles within the product and within the process.

The target capture station, which is somewhat manual, and I'll talk to that later, and of course ultimately a reader, which indicates the results.

So where are we now in terms of pool sizes, and our discussion around smaller pools. Within the U.S., typically, it's a pool size of 16. However, as alluded to, the military and also some other blood centers around the U.S. are doing individual donor testing for HIV and HCV.

If you look around the rest of the world, for Procleix, certainly, the pool sizes have moved down. Europe is predominantly now in a pool size of eight. Brazil is looking at both eight and individual donor testing. Interestingly, Australia is still in pools of 24. However, that is also moving now, and there are strong indications that they are looking at smaller pool sizes.

I wanted to show this because there is a range around the whole world for the pool size. Just one interesting point for those of you who are interested and talked earlier about hospital testing, and sending out of testing donations, Hong Kong actually sends their samples to Australia to be tested and get the turn-around time that they require for blood product release. So it can be done.

What is the trend, though? If we look at the donation volume, and this, of course, bear in mind these are the donations which are currently being tested with one assay, about 10 centers worldwide, using Chiron Procleix which are in the pooling size of 16, you will see there's zero in the individual donor testing, in that range. A higher number, 16, and the trends start to come down this way, with individual donor testing in that site between 103/150,000, European sites in a pool of 7, with a pool of 8, and of course still a high number in pools of 16.

Interestingly, the dynamic changes significantly with, as I'm sure everyone is aware, the European model, certainly for some of the Southern European countries, significantly smaller blood centers, and here a larger number, 52, in the range of zero to 100,000, with 47 of them testing in IDT.

Now, of course, if we're to add on and layer on another assay, a West Nile assay, in effect, you can move these, you can double these numbers. There's going to have to be twice the amount of testing to do the West Nile assay, and that raises significant logistic issues which I'll address later.

Why is the pool size reducing? Certainly, there's a worldwide practice. Interestingly, routine NAT testing now has been shown that, with turnaround times, they are comparable to immuno tests. So, in fact, the NAT is not the great, limiting step for release of blood products. That is allowing people to move to a smaller pool size, taking up some of that slack in the time line.

Pool size is, however, clearly related to test volume. The largest sites, as I showed on the previous graphic, are still using the larger pool sizes, and then recently, in the last few months, the number of assays that are going to be tested, clearly, will influence the decision about whether it's pools or individual donor testing.

Someone earlier identified the area of material availability. Materials can be reagents, can be software, can be hardware. We have calculated, in the manufacturing facility, that we could transition to 100-percent U.S. adoption in individual donor testing of the current product, HIV/HCV, would take about three to six months to build the inventory line.

I think that probably is not the right limiting issue because instrumentation and software could move in a transitional manner to smaller pools, potentially pools of eight, with an approved, FDA-approved or cleared software, within a six- to eight-month time line.

However, probably the biggest issue is the availability of technicians, space, et cetera, within the blood centers and the testing facilities themselves, and also this important issue of project prioritization; is it more important to introduce a smaller pool size now or move to implementing West Nile Virus? Can they do both? In fact, we've had a number of meetings over the last week that's shedding some light on that now.

Instrumentation. Currently, it's modular. However, we're moving forward with the automated, fully automated instrument for nucleic acid testing, and our instrumentation developments are really divided into these two sections: eSAS 2.0 is an evolutionary approach which is gradually automating and removing some of the manual steps out of the process; TIGRIS, which is the Gen-Probe name for the fully automated instrument I'll talk to in a moment.

eSAS 2.0, which is a phased program, the evolutionary approach to it, is building on the current system. I showed the process and the flow earlier and also some of the instrumentation. The aim is to take the most manual steps and automate them. We don't feel that this will significantly improve the throughput. However, what it will do is remove the operator, if there is a marginal operator error, from that process and, also, in terms of throughput per operator, it will improve it, of course, because we're automating those steps, and this sequence here is for an automated reagent tradition station, and that will be introduced to the market for evaluations later on this year, as will the target capture system in the later portion of the year.

Other areas of interest, and these are really driven from the blood centers themselves, as coming to us to ask for these areas, is the automated incubation, removal of a water bath. Water baths in nucleic acid labs are not the most favored item. It would be preferable to have dry heat blocks, for example. So it is very much looking at that area of the technology, but that clearly takes some validation and some time for introduction.

And then, interestingly, leading from some of the questions and comments earlier, having completely integrated data management systems to remove the human aspect of writing documentation down, that clearly is something that we're driving towards. So these are being introduced over the next two to three years as a phased program.

In alignment with that, there is the fully automated process. This instrument is designed to do about 500 tests, and tests, it doesn't matter if it's in a pool or in an individual donation, it can do about 500 in eight hours and up to 1,000 in the 12-hour shift. It clearly has got high focus on GMP compliance, it's got in-built price controls, and this, in fact, has already gone through, last year it went through its diagnostic field studies and also in-house blood bank evaluations, which have been proved to be particularly successful, and we're targeting for the blood screening environment, clinical trials to begin right at the tail end of this year.

Now, I should stress that the clinical trials will obviously be focused on the assays which we've got most experience on and to preempt any question, it would not be focused, at this stage on a West Nile assay. That would be something which would be coming along later on.

Other areas. Dr. Busch referred in his talk to hepatitis B. One of the aspects of the TMA technology is the ability to multiplex. I'd like to just share some data that we have now on the Ultrio assay. The Ultrio is the commercial name for the triplex assay, which is a HIV-1, hepatitis C and hepatitis B product. So there are simultaneous detection of all of these three viruses.

With the sensitivity target of 95 percent, we have got both internal research data and then also data from European sites. Now, this material, the Ultrio product, this was tested last year. This data was presented first at the ISBT meeting, and you can see that, firstly, the HIV and HCV components, the performance is exactly in the range of the currently approved product. So we've managed to add the hepatitis B component without any drift of performance of the current product, and also it's shown again with a target of complete detection of all of the variants of HIV 1, and hepatitis C and B.

What does this mean in terms of window period closure. With somewhat relief, I noticed Mike's data as well, these really are exactly tying in to look at the mini pools, mini pools we've got here of 24. Here is 16, 8, and then individual.

If we look at the pool of 24, this was against the product which was approved within Europe, and we can see, well, if there is some range which would be expected for the panel, that there is extremely marginal benefit over the currently approved and used surface antigen tests.

For about three days here, in pools of 16 and in pools of 8, it's somewhere around the 8- to 12-titer days. In this instance, it was 13 days here. So this is really a reflection on some of the panel data. If you look in detail at it, it was quite a variance.

However, exactly in correlation to some of the data shown earlier, we're looking at potentially up to 30 days, 20 days closure on the current products when using individual, neat sample, individual donor testing.

So that's where we are with the hepatitis B. The West Nile Virus assay, as I indicated earlier, this challenge was thrown out at the end of last year. After careful consideration, obviously, all of the implications of it have been looked at, and where we are is really to certainly take this up to develop and manufacture TMA-based assay.

We looked at it. We carefully analyzed the market situation, and to our mind, and from feedback from the blood services, it was absolutely clear that for them to implement a test under the time line which was being required, basically it had to be based on the current platform. To adopt a new platform, with the change in standard operating procedures, the validation that would be required, that would put immense pressure, actually, onto the system. So the feedback to us came very quickly. It has to be on the current system.

As I indicated, Gen-Pro awarded the further assurance of a grant, and there's really two phases. There's internal data, which I'll show you shortly. What was alluded to earlier, there's going to be some linked donor recipient epidemiological studies, which is in conjunction with the blood services, and we are on target to commence testing under an IND. That's a huge statement when everything has got to be considered around what's still to be involved. However, we are on target with a time line to meet that date.

The goals of the project were to target an analytical sensitivity of 50 copies per mL, 95-percent detection, to be able to detect both lineages, and we have identified a region, a conserved region, that we believe is going to be across both. That is still being confirmed because obviously this is still relatively early stages.

Analytical sensitivity, in the same region, of 99.5 percent, as the hepatitis C and HIV test, and internal control the whole way through the process to ensure that the test itself is working.

Chemistry, that's basically identical, and this is a very important point. Because whilst we can use some of the reagents and some of the chemistry from the current product, clearly, there are areas of probe that need to be changed, but basically with the same chemistry, it allows a much easier training program because the process is going to be very similar, if not identical, to the current product, and that's even down to temperatures of incubation. So there will not be a need for expansion of instrumentation by ways of water baths, for example.

Also, of course, it is being designed to be completely compatible with the current testing platform. So it will be able to be run down the current Procleix systems, and then, as I indicated earlier, targeted to be on our future developments as well.

So how is this performing? I should start off by pointing out that this is on a transcript. This was the initial data. I believe this data has previously been shown at the FDA workshop just prior to Christmas by Geoff Linnen from Gen-Pro. He's the leading research scientist on this project. We can see that at a 95-percent probit analysis, we're showing 7.6 copies per mL sensitivity.

So this is clearly in the same region as we have got for current products. This is a transcript. This was relatively early R&D materials. However, the level of confidence is starting to build around this sort of performance. The importance of this sensitivity I'll show briefly later.

Also, using Lineage I from the CDC as a viral lysate, we have managed to get sensitivity down on a 2.7 times 10 to the minus-6 dilution. Now, I'm sorry, I do not believe that when the dilutions were sent to us, they were actually calibrated, so I cannot equate this 2.6 dilution to an actual level of sensitivity. I don't know if anyone else in the room can shed any light on that.

What I can tell you is that Lineage II is also being sent to Gen-Pro scientists and also calibration of Lineage I is now taking place so that we can reassess these with dilution tests.

Panels. Now this is on Lineage II. BBI have a quality control panel which was available to us at the time. When we did this initial study, they did not have Lineage I quality control panels available. That is also just being developed now, and so you can see there's a whole lot of work going on, bringing all of this together under this aggressive time line.

And we've looked at a number of different formulations, slight differences in probe and in enzyme ratios, and establishing copies per mL, Formulation II and III, which is very similar to the current product. So we, through this process of taking the platform, taking similar reagents or identical reagents, the same manufacturing processes. We are extremely optimistic that we can actually meet this time line and hit the targets that have been laid out.

So, in summary to this area, we have 95-percent detection of the standards at 10 to the minus 6 dilution and a 50-percent detection at 10 to the minus 7.

Again, sensitivity, 95-percent detection at 7.6 copies on a transcript and 50 percent at 3.5 copies.

Demonstrated detection of Lineage II on a viral isolate, and the importance of this sensitivity means that in relation to pool size, those sites, which we're currently using under pooling technology and pooling in 16s, will be able to continue to use those poolings, that algorithm and, in fact, use the same master pool. So they will only have to pool the blood product samples once, and then they can take the samples from that to do the current HIV/HCV test and also followed by the West Nile Virus assay, with minimal changes on the actual instrumentation deck.

As I indicated, we have spent considerable time with the blood services of all representation present. We're very pleased to have work flow studies and work flow work with them. It certainly appears that with the current level of instrumentation, the majority of sites will be able to implement this additional assay on the same test platforms. It could mean some extra staff, which obviously has implications for training, minimal extra instrumentation. However, we are confident that this can be done and the plans are being worked out now for hopefully implementation under an IND in the early summer.

So, to conclude, the Gen-Probe-Chiron alliance is really focused exclusively on nucleic acid testing development. I think the success being shown through the adoption, wide-scale adoption of the HIV1 HCV assay throughout the world, the pool sizes are ranging at this moment in time. However, there is a trend toward lower pool sizes. To complement that and to assist the decisions in moving towards smaller pools, there are two programs of instrumentation--a modular approach, which is taking the manual steps of the current platform and automating them and also moving towards full automation.

Now, we do not see these two systems being parasitic on each other. Because of the size range of the sites, we're seeing that it is very possible that the smaller sites may be less than 100,000, may well want to remain with a semi-automated system which is moving towards this full automation. Whereas, the larger sites clearly have indicated they want to move to full automation of TIGRIS.

This is about as bold as I'm prepared to say. It is on track for implementation in July. However, I would stress, again, through the, the as collaboration with the Agency, there's frequent calls, and there's a lot of work to be done. We're not over the fence yet. There's a lot of work still in the process.

On the HBV assay, the assay development is clearly well developed, it's targeted for a U.S. clinical trial at the end of this year, and ex-U.S., it will be commercially launched again at the end of this year, the beginning of next year.

I just include this because, particularly with the interest that we have had in West Nile, we have got links on their site to a number of sites for hepatitis sites and also we linked to the CDC site as well, and we're getting a large number of visits from this area.

So thank you very much.

DR. BRECHER: Thank you, Celso?

MR. BIANCO: Neil, thanks for such a nice comprehensive view of the program.

I have one question that is essentially pool size, mini pool, individual donor testing. It seems, for instance, that for West Nile, if you want the identical platform, you are sticking to the pool of 16, and certainly it will be very difficult to make a different pool size without knowing, we still don't know what the viremia is.

MR. GUNN: That's right.

MR. BIANCO: The discussion individual donor testing or pool testing wouldn't be part of our business if we had automation. I'd like you to help us understand why, for instance, Gen-Pro got a grant from the NHLBI in 1995. We are in 2003, eight years later, and that promised automation is not here, and it doesn't, I don't hear clearly that that's a priority, as I'd like it to be. Our life would be so different if you had that automation.

Well, I finished my plea.

MR. GUNN: Thank you.

Clearly, automation will change things, absolutely. I think that the progress which I haven't shared here, particularly, but I'll be happy to discuss with people, the progress in the automation has been significant. In the project plan, over the last 18 months, has shown significant improvements.

I think, as everyone knows in the room, development of large platform instruments is a complex task. What was particularly challenging here, this was development of an instrument for a first-generation test, as well. It's extremely unusual to actually develop such a large platform for a first-generation assay. We're confident that it will be there.

I share your frustration, absolutely share your frustration, because I think, you're right, we would not be having this discussion about pool size if automation was present. I think the people would move to smaller pool sizes.

DR. BRECHER: Ron?

DR. GILCHER: I think it is well known that we are doing single-donor, single-unit nucleic acid testing, and our laboratory is performing about in the range of 200- to 220,000 single-donor tests per year. And we had to make that change, as Celso knows, earlier this year and accomplished that, had our operational start-up problems, but clearly are able to do it and have found distinct advantages in performing single-unit nucleic acid testing over the mini-pool testing that we had previously done.

First, we don't have to discriminate a pool. So our quarantine pool size is one. It's made it much simpler. And then eliminating the pooling has given us an incredible turnaround time, our turnaround time being significantly shorter by doing the single-unit testing. And really working with the areas or issues of work flow, we've been able to do it with a limited number of additional staff.

We did have to build new laboratories. We built two mirror-age laboratories to do this, but have the capability in those laboratories of performing 500,000 individual donor NAT tests per year.

So I just wanted to make those comments.

DR. BRECHER: Okay, if there are no other comments, thank you.

Oh, Jay?

DR. EPSTEIN: Thank you very much, Neil, for that very comprehensive account. Could you just clarify one technical mathematical issue.

MR. GUNN: I'll try.

DR. EPSTEIN: If the sensitivity at 95 percent is 7.6 copies and you multiply by 16, that puts you a little over 120, and if the target was 50--

MR. GUNN: Our understanding was that the target is 100 copies in individual donor testing, we're at 7.6 in individual donor testing. Our project goal was 50 in individual donor testing, and we're at 7.6.

Was that--

DR. EPSTEIN: It bears a little further discussion, but, yes, sure.

DR. BRECHER: Thank you, Neil.

We'll now move on to the Roche platform, Paul Chapman.

DR. CHAPMAN: I just have to do a quick swap-out here, if I may.

[Pause.]

DR. BRECHER: Why don't we just take a 10-minute break while we're changing computers.

[Recess.]

DR. BRECHER: Let's begin.

Paul, if you want to start, dive right in. They'll trickle in.

DR. CHAPMAN: First of all, thank you to the organizers for inviting me to speak on behalf of Roche Molecular Diagnostics. I'm going to be discussing the Roche blood screening program and its priorities.

Now, in the absence of having the ever-elusive crystal ball that can help us determine what the virus de jour is going to be downstream, we at Roche have had to prioritize based on current needs of our customers, as well as near-term needs, and then do our best to determine where that's going to take us five to ten years down the line.

The current mean priorities for Roche right now are HBV, West Nile Virus, obviously, full automation, which has also been discussed today, the single-donor testing, and also Parvo B19 and HAV.

First off, and those are in the order of priority. They're number one priorities for us.

The COBAS AmpliScreen HBV PCR assay, those, some of you may or may not be aware that our COBAS AmpliScreen system for HIV and HCV recently was granted FDA approval.

Our HBV AmpliScreen PCR assay has been designed for use on the same platform. The way it works is one single extraction extracts for all three targets, HIV1, HCV and HBV.

We have already been in clinical trials now since August of last year under IND. To date, we have tested upwards of 300,000 donations, and we're very excited to announce that we have two confirmed window cases already detected in pools of 24, giving us a hit rate of 150,000.

Also, it was shown earlier as well that it comes into question for HBV testing how it would compare against the PRISM assay, and nonclinical data in pools of 24 suggest that we, this is the European PRISM HBV assay, that we get a 15-day gain in diluted samples 1 to 24.

So it's clear to us that the IND window cases that we have under our IND should indicate that the HBV assay in pools could add an incremental level of safety to the blood supply. A challenge for us is that we now have to continue and close out this trial. It's expected to close 2/2/2003, and all of the folks that are working diligently in development of regulatory clinical trials, closing this and preparing this submission, are the same folks that are working diligently to get West Nile out the door as well.

So we can, at this point, only assume that the data here would support an FDA-approved assay, we're hoping, and that there will be a mandate to actually test for it, once approved.

Dr. Chamberland gave an excellent overview of the West Nile Virus situation, so I need not go into the details of why we're doing this, just to comment that the threat has resulted in an unprecedented effort from industry, both from a resource perspective and a time-line perspective, that we are embarking on something that--and on the next slide I'll elaborate on it--that is extremely unprecedented for us and for the testers and even the regulators.

I can say that we are definitely committed to implementing a nationwide IND by July 1st, 2003. We are confident we're going to hit that date, and our confidence stems from the fact that we're incorporating synergies from already-existing platforms and, also, Dr. Chamberland, in her presentation, discussed the PCR TaqMan technology that's already being used in research, and we're elaborating on that as well.

Our preferred system for West Nile is the system you see here. The COBAS AmpliPrep and the COBAS TaqMan, the COBAS AmpliPrep is generic capture, fully automated extraction, and the COBAS TaqMan is 5 prime nuclease real-time amplification and detection technology--again, the same technology you heard described by Dr. Chamberland.

The big challenge in a nutshell is that we're doing this in a nutshell.

[Laughter.]

DR. CHAPMAN: Ultimately, this is a two-year program in a normal case, and we're being asked to complete this in about a nine-month time frame. So that involves everything from assay research and development, platform adaptation, installation and training at the sites, validation, our IND submission and approval, and then to go live by July 1st, 2003.

There are still issues that need to be resolved in terms of after we go live along the lines of donor follow-up, given that the epidemiology of the viruses is not fully understood, we think that harmonization between the IND holders would go a long way to help us try and understand the epidemiology of the virus better.

As far as our fully automated platform, and this is speaking to the needs to get full automation, not only to decrease potential human error, but also to move towards smaller pool sizes or even single-unit donation testing. Our requirements are that it be fully integrated through process automation, throughput that accommodates single-unit testing obviously, 100-percent positive sample ID throughout the process.

Again, our platform will use generic capture, which is foundation technology that you saw two slides ago--generic capture on the AmpliPrep CAPG and homogeneous TaqMan technology.

We obviously have to have the ability to multiplex RNA and DNA viruses, and we need to make sure that this system for long-term use has flexibility for menu expansion.

We are confident that we can move rather quickly with a fully-automated single-donor platform, again primarily because of our experience and synergies that we have with existing technology in the AmpliPrep and the TaqMan platforms. And from an assay perspective, we can benefit from our experience with our AmpliNAT assay, which is triplex, HIV, HCV, HBV, TaqMan assay that's been in use upwards of four years in Japan.

We also draw on an extensive multinational development team with assay development being both in Pleasanton, California; Penzberg, Germany; and then we have our own instrument center, our own instrument developers who are the developers of the TaqMan, of the COBAS AmpliPrep and of numerous chemistry instruments in Tegimenta, Switzerland.

Mike discussed Parvo B19 and HAV earlier today. Our platform that we've developed is designed primarily for the in-process model that Mike showed. This technology again uses TaqMan on the back end with the LightCycler, and its generic extraction on the front end using the MagNA Pure, generic extraction.

Again, this is for in-process testing, and a challenge that we see for implementation of Parvo HAV, again, this is reiterating what Mike said, is the priorities, both in blood and plasma centers, and current guidance from the FDA is that this should be an in-process test right now.

As far as we're concerned, a logical step for us, because, again, this is TaqMan technology, we can transition that to the platform that you saw a few slides ago, the CAPG TaqMan, to make this a screening test, but the question remains is screening for Parvo HAV in the public's best interest as a front-line screen or will in-process testing suffice for now, and we would need more guidance from FDA on that.

Now, PCR, because it's so widely used in research, lends itself to relatively quick turnaround, if you will, for a menu expansion, and I have a list here of a number of potential assays that I know I've been asked at least once or twice as to Roche's involvement and commitment to the development of these assays. They can be anywhere from bacterial contamination of platelets, leukoreduction, QC testing, Chagas, babesiosis, malaria, CMV, HTLV I and II. These assays, incidently, from my days at the affiliate in Canada, were on our product list. So these actually do exist, just not in a blood-screening capacity.

Those of you that may or may not know of the anthrax collaboration with Roche Diagnostics Indianapolis and the Mayo Clinic, on the same platform that you saw for Parvo, they developed an anthrax assay. So, again, it's the research moving into IVD and the quick turnaround time that could potentially be of use in bioterrorism response capabilities.

Hemochromatosis is another one that we've been asked about and ultimately just insert emerging pathogen here.

[Laughter.]

DR. CHAPMAN: We don't know where it's going to take us. Again, if we had that ever-elusive crystal ball, I'd be able to fill in that blank.

So, in summary, what I hope I've conveyed here is that even in the face of competing priorities, Roche is extremely committed to improving the safety of the blood supply through its PCR technology. Again, the fact that PCR is widely used in a research mode enables us to turn assays around quickly, hopefully, and I think the proof is going to be in the pudding with the West Nile Virus assay development.

I think that West Nile will be a perfect case study for developers, testing facilities and regulators and what we can do with a little, and a little might be an understatement here, but with a little flexibility and determination.

Thanks very much.

DR. BRECHER: Thank you. This presentation now is open for comments and questions.

Celso?

MR. BIANCO: Paul, I have to be fair and ask you the same question that I asked of Neil Gunn.

With a Roche company, a global company with superb resources in terms of equipment, manufacturing, lots of automation and clinical labs, honorable history, why don't we have automation yet?

[Laughter.]

DR. CHAPMAN: You mean full automation, right, Celso?

MR. BIANCO: Correct.

DR. CHAPMAN: Because we do have automation--

MR. BIANCO: Automation in terms that we in transfusion medicine, the people that are looking at zero risk and all of that, there is a total control CGMP of the materials that we have so that we are sure that the sample that got into the machine corresponds to the result that got out and that the result is accurate, with minimal operator intervention, minimal opportunity for human error.

DR. CHAPMAN: The full automation solution is something that we are fully dedicated towards developing. One of the slides that you saw, in essence, is full automation, which is the CAPG AmpliPrep instrument Department of Commerce 2 TaqMan. That is full automation. Whether it would fit in a single-unit testing environment, remains to be seen. Would it fit in a lower pool-size environment remains to be seen.

All I can say is that it is a major priority for us, along with the other priorities that you saw, and our hope is that, given the foundation of our platforms that we have to work from, this should be a positive, reasonable effort moving forward.

DR. BRECHER: Jay?

DR. EPSTEIN: Paul, you probably would have said this if you had wanted to, but could I press you whether you have any data on the sensitivity of a prototype test for West Nile?

DR. CHAPMAN: Yes, I did realize I was data light here for you.

The initial that we have back, and this is very preliminary, and I think you're going to see a lot more in terms of data at the BPAC, is we have better than 30 copy per mL sensitivity, and we're targeting a lower pool size than pools of 24. I can't tell you that right now because we haven't locked in on it, but it's going to be lower than 24 for sure.

DR. BRECHER: Any other questions or comments?

[No response.]

DR. BRECHER: Thank you, Paul.

DR. CHAPMAN: Thank you.

DR. BRECHER: Our next NAT talk is on source plasma. Gerold Zerlath?

DR. ZERLATH: Good afternoon. First of all, I would like to thank the Committee for inviting me to give a presentation on NAT testing for source plasma. I'm talking on behalf of PPTA, and I'm employed with Baxter Bioscience in Austria and Europe.

NAT has drawn a lot of attention, and it's not surprising because that's a very interesting new testing platform, and those of you who have attended scientific meetings over the past years have been exposed to a lot of details concerning sensitivity, and specificity, and primary design and so on and so forth.

So, actually, I think that most of you could be called experts, and I will not elude too much on the test system, as such, but I would like to give you an idea how the plasma industry is using NAT in the context of its viral safety programs.

I also would like to point to the fact that I'm talking about source plasma, and that's quite different from what we have heard in the transfusion scene, and I will allude to that, to some degree, because as we deal with the same ingredients, human-derived material, plasma, and as we use NAT test systems, we still employ those tools in a quite different format. I would like to show you the basics, the idea behind it, how we have implemented that and what the outcome is.

So a plasma safety program can be roughly, in the plasma industry, can be roughly divided in three parts. One, our activities that are donor targeted, and by those I mean the appropriate site selection, paying attention to the viral market rate at the given area, drawing blood in the most appropriate areas if possible, doing medical checks to avoid the donation or the drawing from sick donors.

We have questionnaires to filter out people that may not be suitable for donation. We have a qualified donor program, and by that we mean that our donors need to or have to repeat at least a second time. We do not accept first-time donations. We request people to come back and hopefully remain repeat donors for over a long period of time, and of course we apply to the NDDR system.

So these measures, in brief, are thought to be taken to select the right site and the right donor, and then we have, of course, a whole battery of donation-directed activities. This is, of course, testing serology and NAT, and I will allude to that in more detail. But in addition we do have inventory hold, by which we mean the usage of any given donation not earlier than two months after bleeding, and then, of course, we have lookback activities which enable us to trace previous donations back in time.

Now, at that point, we have already the first difference to the blood transfusion service because we can have inventory hold, we can keep the donations over time, and from here on, and the donation at that point is actually our starting material and not the final product.

In addition, we have, of course, means and steps during production where we can take care of any virus that might have escaped our attention and enter production. We have killing and removal activities which I'm not alluding to, but just for the complete picture, I would like to show that.

Now, with this program on hand, we can use NAT as one tool, as one tool in our toolbox, and we can combine that in a diligent way by using NATs, serology, inventory hold, lookback and qualified donor in a way that helps us to overcome all of the shortcomings that have been alluded to and that I will show you in detail in a second.

I just would like to draw your attention to the two voluntary programs that we have within PPTA, where our member companies adhere to--that's IQPP--mainly voluntary standards which rely on the blood-drawing or plasma-drawing site, and QSEAL, which is more directed towards testing, inventory hold and those practices.

Now, as you can imagine, and I don't want to allude to that in great detail, we have the whole serology test portfolio, some of which are specific for countries like Germany or Austria have different regulations to the United States, and Sweden again has another set of requirements, but, nevertheless, to play it safe, we usually apply all the tests, and that actually adds quite a bit to our test portfolio.

The NAT test portfolio within the PPTA member companies, those who adhere to the QSEAL Standard, is NAT testing for HIV, HBV, HCV and Parvo Virus B19, and we will soon add HAV to the portfolio testing for all of the five viruses. Some of our member companies already do test for HAV and others will soon adhere to it.

As I said, we have inventory hold, lookback and post-donation information, and I'm going to show you how we are using that to increase the safety margin for our products.

As it has been alluded this morning already, the diagnostic window is the crucial part in the whole game here, and as we all have seen, it takes some time until antibodies or viral marker develop after infection has taken place, and we have no chance to detect the presence of virus through secondary markers, a situation that is different if we target the virus, the infecting virus itself. This enables us to shorten that window, and Mike Busch and others have shown already in more detail how that works.

I just have this slide as an underlying picture because I would like to show what this reduction of diagnostic window time can do for us in the frame of the plasma industry.

If we assume that a qualified donor, and here it's very important to emphasize the fact that a donor returns repeatedly to donate, if a qualified donor comes back to the center, say, once a week and donates, and then after some donation gets infected, let's assume for HCV, we do not have a chance to see this infection because of this diagnostic window, and this window can be significant from three weeks to three months, depending on the virus and, of course, depending on the host and other factors, but overall it can be a sizable time span.

And in this time, the donor returns, say, every week and donates, and whatever we test by serology, we absolutely have no chance to see that infection because of the absence of antibody or the level being too low. Only when the antibody level reaches a significant amount that enables us to detect it, we have a chance to intercept that donation and to defer the donor, but we have received a significant amount, several donations which already do contain virus, and we have no chance to see that.

Now, being aware of this fact and in the absence of NAT testing, we have introduced a measure which we call inventory hold, which is, as I said, the usage of any donations not earlier than two months after bleeding, and that, in fact, enabled us to intercept donations once we detected the presence of viral markers, and we could take these donations out of the system and preventing, thereby, the virus entering our production lines.

Now, this system is not perfect because two months is not enough of a time span to really get hold of all the donations, and this put us into the situation that we might have added virus-containing donations, which, of course, followed by antiviral activities during the processing of the plasma product could be taken care of. But we did not--we never knew how much virus we are going to see, and, therefore, that's an uneasy situation because the system could become overwhelmed.

Now, with NAT in place and the shortening of the window, the diagnostic window, the situation became immediately became much more favorable because we can obtain a significant reduction in this window phase, and we again have seen a lot of data during this meeting here. But, nevertheless, most pronounced for hepatitis C can be between 41 and 60 days of gain, depending on the size of the pools, and depending, of course, on the sensitivity of the assays.

In any case, we will be able to intercept a positive donation much earlier, and by this we save a lot of positive donations to come into our system. And if we also add inventory hold, which is the case, of course, in our everyday business, we can now intercept donations actually such that we even get hold--under theoretical conditions, we get hold of donations which have been donated prior to infection. And that makes an extremely safe and powerful system in avoiding virus entering our production pool.

What we also can see and deduct from that sort of drawing is that our minipool approach--and most of our companies stick to a minipool size of 512 donations--is sufficient for the purpose because the ramp-up phase of virus once replicating is so rapid; and given the fact that we have repeat donors, we actually have the situation that maybe today we won't even see it in single-unit PCR, but say four or five days later, when the donor shows up again, not being of the infection, we already have a very good chance to see the positivity, even in a minipool size of 512. And I'll show you the data which corroborate what I'm saying here.

Now, having an idea is one part, but to integrate that into a testing scheme is not trivial, and it takes a lot of logistics. We are receiving about 200,000 samples per month, and that is really a logistical challenge. But for each donation, we not only receive the donation but, as I said, we receive an aliquot in a vial for testing purposes, and these vials are pooled automatically into pools of 512. And I'll show you in a little bit more detail how that works in a second.

We call that a minipool, and as I said, this is an aliquot. We have not yet touched the donation. This is an aliquot of the donation. We subject that to NAT testing, and if this NAT testing of the pool of 512 is non-reactive, we clear the corresponding donations, and if inventory hold period is over, those donations can be used for forming a production pool.

The production pool again is tested by NAT, but this is more a quality assurance measure just to make sure that all the right donations have been removed. And in addition, it is a regulatory requirement in Europe because the production pool is the test of record, and we are obliged to test the production pool by NAT for hepatitis C virus. And the German authority is about to introduce also the obligatory testing for HIV, should occur during this year.

Now, if a minipool turns out to be reactive for one of those viruses I have been talking about, we start a minipool deconstruction process and test the subpools, and I am showing you in detail how that works. Basically we are forming subpools. You should consider each of these squares or cubes actually an individual sample. And we form subpools of eight times eight individual samples, one time in a layer fashion, so we get eight vials of eight layers. And then we do the same thing in a column fashion, and we get eight vials which are the column subpools. And then we do it again, and we do it in a row format, and then we get eight vials which represent the eight rows. So, in fact, we have eight times eight times eight. As a whole this makes 512, and then eight and eight and eight makes 24 subpools. So with 25 vials or 25 tests, we can identify the individual donation which is positive within this pool because, since each donation has to be contained in one row, in one column, in one layer subpool, the crossover point is the donation concerned, and that's remarkably stable. But it only works if you have not more than two positives in one set, which normally is the case for HIV, HCV, HPV, and HAV. It's a little bit different in parvovirus where we may have up to 15 positive donations; then, of course, you run into many crossover points, and some of them are blind or empty. But in this case, this doesn't concern us because we do not verify parvovirus positive once, but we do verify obviously positive donations for the other viruses.

Now, with this deconstruction system, we identify the positive donation, and that gives us a hand to identify the real donation, get hold of it, verify its positivity, and, of course, go back via lookback into our inventory hold and pick up all the previous donations that are still available and also those are taken out of the process and destroyed. And after this, we again form the production pool from the suitable donations, and as I said, test it by NAT in order to have this requirement from a regulatory point of view and for obvious quality assurance reasons, making sure that we pulled all the positive donations that we identified.

Now, let me show a few results. I have chosen results that comprise U.S. plasma only, and those data were obtained in the frame of an IND, including data from April 2001 until December last year. We have tested 4,883 minipools, which times 512 make about 2.5 million donations which were included in these minipools. We have found 89 positive minipools for hepatitis C virus, and each case was without anti-HCV antibodies, and, of course, earlier detected than the (?)-ority.

The rate of positive donations--and I have to put a lot of emphasis on donations--is 1 in 28,000. We do not know how many donors are involved because this is still blinded and we do not know how many donations have been derived from one donor coming in consecutive bleeds versus single donations in a pool. So all I can give you is the rate of positive donations in this scheme.

For HIV, we have found two NAT-only positives, which is 1 in 1.25 million. And for hepatitis B virus, we have found three donations--or three minipools, which is 1 in 830,00. And, again, of course, this is the rate of positive donations in the given scheme, doesn't tell you anything about how many people are involved. We need to wait for being unblinded, this IND; then we can tell more about the number of donors involved.

Just for your interest, we have, of course, in the same subset of tests but not within IND, obviously tested for HAV, and we have found again two positive minipools, which, again, is 1 in 1,250,000. And parvovirus B19, we found 191 positive minipools where the minipool positivity is seen as greater than 1 times 105 international units per milliliter. This actually is about 4 percent of our minipools, and that we already have published in 1999 at the FDA Parvovirus Workshop, and it's remarkably stable over the years that about 4 percent of our minipools contain high-load parvovirus donations. And in this case, as I pointed out earlier, I cannot give you a rate for the positive donations because we intercept several donations which are not positive but just happen to sit in the crossover points, and we take them all out and do not verify the data. We just take out the donations and carry on.

To complement what I have shown to you, because those data are derived within our own enterprise, I have here a slide which I took off the website of the Paul Ehrlich Institut, the German health authority, and, of course, with authority documents you don't fool around, so I left it in German, as it is there. But I think it's easy to get the idea.

As I said, Germany and several other countries in Europe require hepatitis C NAT on production pools to be done, and you are required to send in a sample to this institution, and some of those are retested by the institute, and they find out whether you supplied the right thing and did the right testing. And prior to the introduction of hepatitis C NAT, they had three companies, which they called C, D, and F, and between 20 and 40 percent of the submitted production pools have been positive for hepatitis C virus by their NAT test; while after the introduction of the obligatory HCV NAT testing, they found none in the cases given here. You can find that on their website. It's original.

So, in summary, I think we can say that with strict donor selection and applying the qualified donor program, applying serology testing, having inventory hold in place, and having validated virus removal and inactivation steps, we were already ready to make very safe products even in the absence of NAT, and NAT in a minipool format, as we apply it throughout our member companies, has greatly, in my opinion, improved the safety margin, and I think the data that we have now since '99, '95, and some 14, 15 million donations tested and no incidence since prove very well that the minipool format chosen in the frame of the other tests that we apply for achieving safe products have proven to be adequate and appropriate, and also quite important, feasible and affordable.

Thank you for your attention.

DR. BRECHER: Thank you.

Questions? Comments? Celso, you do you want to ask about automation?

[Laughter.]

DR. BIANCO: They don't need it. Their pools are pretty big. But what Gerold, I think, pointed out that is very important, the intent of the testing is so different in a plasma fractionation from that of the selection of blood donor. They're looking to reduce the viral loads in a pool, and we are looking for a negative unit, and that's what makes it difficult.

DR. ZERLAUTH: But I am disappointed you're not asking me about automation because we do have automated parvo PCR.

[Laughter.]

DR. ZERLAUTH: We don't touch the sample anymore. That is fully automated for parvo.

DR. BIANCO: But not for HIV and HCV.

DR. ZERLAUTH: That will come soon.

DR. BRECHER: All right. Well, thank you.

For those of you who have lasted the day, we've saved something good for the last, and Jim AuBuchon is here and he will be giving us an overview of prioritizing risk and transfusion medicine. Professor AuBuchon?

DR. AuBUCHON: Thank you very much, Mark, and I'd like to thank the committee for their indulgence in changing the order of the presentations to allow me to attend to some matters at home before coming this afternoon.

Mark asked if I would provide some assessment of the risks of transfusion with an attempt at prioritization, and I will attempt to do that with a perspective from the bedside. I'll give you the perspective of someone who's intimately involved with the delivery of transfusion medicine, hemotherapy at the bedside on a daily basis.

My perspective about what patients are worried about can be easily summarized. I think despite all of our advances that you have heard about today in terms of improving the safety of components that are transfused, it has not dissuaded patients from being concerned about HIV transmission in transfusion. And most patients think that if they're lucky and they avoid AIDS with a transfusion, they're likely to get hepatitis. And, of course, those who read the New York Times are worried about variant CJD transmission. Of course, the truth of the matter is far different.

Most patients want a very simple question answered, that is: Will this transfusion be safe? And they want it answered in a very simple fashion. They want a yes or no answer. They don't want to hear about pool sizes. They don't want to hear about the titer of a particular West Nile virus that can be detected using new technology. They just want to know: Am I going to get through this transfusion without coming down with something that I don't want?

Clearly, we have been paying much attention over the last two decades in transfusion to selecting the appropriate donors and doing whatever we can to test the unit to ensure that units that are actually collected do not transmit any agents. This is very important and clearly has been the mainstay of providing safety of the transfused product.

However, over the last several years, I've been very gratified to see that the transfusionists in this country and those who support them have begun to accept the success that they have had on the left side of this picture--that is, in terms of providing a safe unit--and come to recognize that the residual risks that we face now for transfusion lie in other others; that is, they aren't related to viral transmission. They're related to a number of other things in the transfusion process, that the process of getting a transfusion involves multiple steps, and all of these need to be accomplished correctly every time in order to make sure that the benefit of having a unit that does not transmit an agent does not go unnoticed because of something else that goes wrong in the entire process.

Slides like this that you have seen today showing the huge reduction in the risks of the viral agent transmission are indeed testimonies to the success that we in transfusion medicine have been able to have through the cooperative effort of many individuals, particularly from industry and developmental science.

I would hasten to point out that the y axis here is a logarithmic scale, so we're looking at something on the order of 4 log reduction, 4 orders of magnitude reduction in the risk of the major viral agents over the last two decades. That's a success story.

The question, of course, still has to be answered: How much protection do we need? How much protection does the patient want? We come up with multiple barriers to prevent an agent such as HIV from reaching the patient. But just how thick do these brick walls have to be before the bullet doesn't reach the patient and that we can guarantee the bullet will not reach the patient? Obviously, guaranteeing a zero risk is an impossibility still today.

If we overlay the slide showing the reduction of risk of the major viral agents with other concerns of transfusionists, you can see that there are many things that can go wrong in the transfusion process that have a much greater likelihood of causing morbidity or mortality in the recipient than HIV or HCV transmission. I will come back to this point multiple times in the presentation, and I would like to dissect this and talk about some of these individual risks. But many of them, most of them, relate to the transfusion process. That is, we have to make sure that everything that is done in the hospital, from patient identification to identification of the sample from that patient, to the testing of that sample, to the release of the appropriate unit and return to the bedside of the correct patient with the unit intended for that patient--all of these steps must be conducted appropriately, or the safety of the unit is lost.

So what are some of these other risks and how do they compare? Certainly transfusion reactions have been known for over a hundred years, and two of them are certainly relatively common that we face every day in any hospital transfusing blood.

Urticarial reactions are usually more of a nuisance to the patient and a disruption to the care of the patient than anything else. The hives and flushing that go along with these reactions do not cause any severe morbidity, but they're clearly uncomfortable. They're related to incompatibilities with the various plasma proteins that may be in the component, and there's no good way to avoid these in plasma-containing components.

Febrile reactions still occur with some frequency, as you see there, somewhere between 5,000 and 10,000 per million units transfused. That's an uncommon way for transfusionists to talk about febrile reactions because they occur at something on the order of 1 percent frequency. But you'll see shortly why I'm using the denominator of per million units.

Febrile reactions, of course, occur in those individuals who have been sensitized to leukocyte antigens. They can be avoided with the use of leukocyte reduction technologies, and in those patients who are multiply transfused, this is the approach that is commonly used. And for those centers that use universal leukocyte reduction, the avoidance occurs because of the universal application of that technology.

Those are not the major concerns, however. Bacterial contamination you've heard about already--and you'll be hearing about it tomorrow in greater detail--certainly does occur at a significant rate, somewhere around 1,000 occurrences for every million units of platelets transfused. Transfusion-related acute lung injury--we'll talk about that a little bit later--occurs at a rate of about 200 per million. Mistransfusion--that is, a unit going to the wrong patient--occurs at a rate of about 1 in 12,000 or 83 per million units. And a fatality due to a bacterially contaminated unit occurs at a rate of about 7 per million units transfused.

Compare that to the risk of HPV transmission, about 5 per million units; HCV, around 1 per million units; or HIV, about a half an occurrence per million units transfused. Greatly different. And, in fact, to look at some of these magnitudes at the lower end of the scale very closely, you indeed need a magnifying glass--my apologies to USA Today--in order to really see what we're talking about, because these risks here that we often talk about--HPV, HCV, and HIV--are today vanishingly small. But when you compare them closely to bacterial fatalities or even fatal hemolysis, you see that these other issues are at least as large as, if not larger than the things that grab the headlines, usually.

Of course, there are numerous other pathogens that are under surveillance. We've heard about West Nile virus today, which we certainly know is transmissible via blood components. And we're all glad to hear that various manufacturers are working on ways that we'll be able to detect those donors who might transmit West Nile virus by next summer.

TTV and SEN-V are transmissible viruses of unknown pathogenicity, but they are quite prevalent in the donor population in multiple countries. We may have to worry about those. We are not certain that we need to worry about them today.

Human herpes virus VIII may be transmissible and may well be pathogenic for immunocompromised patients. It has a significant prevalence. It is something we need to worry about.

Enterovirus may also be transmissible, some strains of which are pathogenic. The prevalence is also significant, about 1 in 5,000, at least in one U.K. study.

Malaria also we know is transmissible, as is babesiosis. There are relatively few fatalities related to either one of these diseases, but the frequency of several cases per year in the United States for both malaria and babesiosis is still something that is talked about when we are discussing risks with clinicians ordering transfusion.

Chagas disease is something that blood bankers are certainly concerned about. There have been nine cases transmitted in North America. There, of course, is gestational transmission as well. The frequency of occurrence of the parasite is not insignificant. One study showed it to be about 1 in every 600 Hispanic donors. That would calculate out to about 500 donations a year in the United States having Chagas disease.

So these are all pathogens that we need to be concerned about beyond HIV, HPV, and HCV.

I'd like to spend a few minutes talking about some of these in a little bit more detail and focus on bacterial contamination for a moment. There have been a number of studies attempting to document exactly how frequent bacterial contamination occurs and what's the clinical outcome of transfusing a contaminated unit. Many cases of bacterial contamination go unreported because they are unrecognized at the bedside.

Patients who need platelets are often immunosuppressed and neutropenic and, therefore, when they have a fever after transfusion or become septic after transfusion, the clinical team may not recognize the source of the offending pathogen.

Also, many of these patients are receiving antibiotics, and so a response to the exposure to bacteria may be blunted. But the very thorough Haemovigilance Study from France documented that the rate of fatality--not just occurrence but fatality--was 7 per million units.

Now, the CDC's Bacterial Contamination Study that has been reported several times in the United States, most recently last year, noted a lower risk, but I think that related to the case definition which was much more stringent and often difficult to achieve, and because of the voluntary nature of their reporting system. But, still, there are a significant number of deaths that the CDC was projecting based on even these incomplete data.

But the risk from the French study would calculate out to about 1 in 140,000. Again, an order of magnitude greater than the HIV risk.

Another study reported from Johns Hopkins I think points to the direction that this is indeed a significant risk. The risk is different if you're using platelet concentrates versus single-donor platelets related primarily to the number of donor exposures. But you can see here the risk in terms of somewhere between 14 and 62 per million as compared to, again, HIV at about a half per million.

So for the United States, where we use about 50 percent apheresis products, this would calculate out to something greater than 100 patient deaths per year due to bacterially contaminated products.

Turning our attention to another risk, and that is mistransfusion, patients getting the wrong units of blood, and then suffering an ABO acute hemolytic episode and potentially dying from that. Mistransfusion is a common problem in all developed countries. One-third of all United Kingdom hospitals reported a mistransfusion during a two-year study period--one-third--and the wrong blood was found in the pre-transfusion testing sample about 1 in every 6,000 sampled. Their risk of death, about 1.5 a million, is not dissimilar from what has been reported from this country.

During the first two-year period of reporting from the serious hazards of transfusion study in the U.K., of the 366 reports of a serious hazard, over half were related to an incorrect blood transfusion. This is just the tip of the iceberg because, of course, there are near misses as well where it happens that a unit is given and it is not intended for the right patient or the sample has been mislabeled, but it happens to be a compatible unit. So you can see that the true error rate is substantial.

The Biomedical Excellence for Safer Transfusion Working Party of the International Society of Blood Transfusion conducted a survey of this issue last year, reported at the AABB meeting by Sonny Dzik and Mike Murphy. They noted on an international basis that the wrong blood was in the tube--that is, the sample coming to the transfusion service was labeled with the wrong patient identity--about 1 in every 1,000 times.

Now, this goes along very closely and supports the data that have been reported to the idea and reported from the FDA. For example, Jung Lee reported at the BPAC meeting several years ago, noting that in an eight-year time period there were 161 fatalities reported to the FDA. And, undoubtedly--I'm sorry to report, Jay--this is an underreporting. Not all of those cases indeed get reported, as they should. But that accounted for about half of all the fatalities that were reported during that period: 161 in eight years. How many HIV transmissions did we have during those same eight years? Far, far fewer.

What is the cause of these problems? Well, related to two sources: one, mislabeling of the sample at the time of sample collection, and administering the unit of blood to the wrong patient. These data that Kathleen Sazama gathered from FDA files document that giving the unit to the wrong patient is the primary cause of these fatalities. Of course, Jeanne Linden on the committee has also been a prime mover in identifying this as a problem. And a survey from New York State hospitals documented that 1 out of every 12,000 red cell units goes to the wrong patient. This is a worrisome number because this is the number of red cell units that we transfuse each year at my institution. And I certainly would not want to have a mistransfusion occurring annually. But yet it certainly could in any institution in this country.

Dr. Linden also noted that the primary problem, as Dr. Sazama has noted, is failure to identify the patient properly at transfusion or labeling the sample incorrectly, those two issues accounting for over half of the mistransfusion events.

Clearly, what is needed is a compatibility testing system that takes into account all the different factors that lead to proper identification of the patient and selection of a compatible unit--again, beginning from the patient and labeling of the sample appropriately to identifying the recipient at the time of transfusion.

Now, I've often shared this calculation with my colleagues who think that it never happens at their hospital. A study published several years ago in Transfusion from a U.S. hospital noted that 1 out of about 3,000 samples contained blood from a patient whose name was not on the tube. It was a different patient. And I then add that these data don't come from a St. Elsewhere that didn't have good systems or didn't have smart people paying attention. These data come from Johns Hopkins. And if Johns Hopkins can't get it right any more frequently than this, why do the rest of us think that we have any better system?

There certainly are systems available to prevent mistransfusion. They are woefully underutilized in my opinion. There are both simple blocks that act as a mechanical barrier system, and there are more modern electronic systems that will allow positive identification of the patient at the time of sampling, and correlation of that identification with the transfusion recipient identification and the unit labeling at the time of transfusion. Unfortunately, very few hospitals are using these devices today, and we are still killing about two dozen patients every year in this country by giving them the wrong unit of blood.

Another concern that has gotten more attention recently is that of transfusion-related acute lung injury. There are some patients who suffer an acute post-transfusion decompensation of their oxygenation capability, which is essentially respiratory distress syndrome in an adult. The most common etiology is the presence of anti-leukocyte antibodies in the donor that react with the recipient's white cells. So this is not something that leukocyte reduction is going to help, unless you want to leukocyte-reduce the recipient. We don't have a good way of identifying the units at risk or the recipients at risk for a particular unit. The frequency is estimated at about 1 in 5,000, but this is undoubtedly an underreported event as well.

Now, the outcome is usually tolerable, although it often involves a trip to the ICU for several days of ventilation support. But the fatality is often spoken of as being relatively low, only 5 percent. But let's do the math. If the frequency is about 1 in 5,000, there are at least a thousand cases which occur annually in the United States, and you multiply that by the 5-percent fatality, and you're dealing with at least 50 deaths annually. So, again, this is a substantial risk for patients receiving a transfusion, something that I'm sure most patients have never heard of and probably goes unrecognized very, very frequently when it does occur.

And since this is the Advisory Committee on Blood Safety and Availability, I would also like to point out that there are risks involved from the steps that are taken to improve the safety of the blood supply by restricting who can donate. This committee saw data three years ago presented by Marian Sullivan from the National Blood Data Research Center which really raised a huge question: Were we about to run out of blood? Because based on the data that were then available in terms of availability of blood and usage of blood, it appeared that in the year 2000 these two lines were going to meet. Obviously they can't cross, but they were going to meet and that we were going to have not just occasional spot shortages or seasonal shortages, but ongoing chronic shortages. This is a major concern because lack of blood is a safety factor. If you don't have blood to transfuse when it's needed, the patient will not be cared for optimally.

And we already have difficulties in providing enough blood. These are data from several years ago, but trust me, they haven't gotten any better. Nine percent of hospitals three years ago reported at last one day on which they had to cancel or postpone elective surgery, and the median was two days. Twenty-five percent of hospitals reported at least one day when all non-surgical blood requests could not be met. So, clearly, there is an ongoing problem of not having enough blood, and simply raising the bar to say we are going to exclude certain donors in order to make the blood supply safer has some costs that relate to the availability of blood for transfusion.

So to return to this slide showing our success with certain viral agent and yet the persistence of other risks that today clearly are much greater than the HIV and HCV risks that we usually talk about, where's the problem? Well, there are a number of problems here. The interventions that we could take to solve some of these problems or address some of these problems cost somewhere between a few dollars per unit to maybe $100 per unit. We don't know what pathogen reduction technologies will cost, but it's probably closer to that larger number than the smaller number. And whatever the per unit cost is, one has to multiply that by the millions, tens of millions of units that are collected every year in this country, multiplied by 14 million for any testing, and some 20 million components that are transfused.

The health benefit yield that will be seen from any particular intervention is going to be relatively small because of the infrequent occurrence of these untoward events. And, of course, patients who are receiving transfusion already have intercurrent mortality that we have to include in the calculation of any benefit. So we don't necessarily see huge yields in terms of life years gained or in cases avoided until we start comparing it to some other events that could occur.

We also have to recognize that part of the problem is the hospital payment for blood components, particularly as they become more expensive and as new technologies are added, is insufficient. There's an article that I would commend to the committee's reading from the CAP Today, a publication from the College of American Pathologists last month, that talked about the pay gap that is really a barrier for hospitals to adopt new technologies to make the blood supply safer.

Now, I would like to digress for a few moments and talk about why the public, in my opinion, is still so interested in blood safety, because, frankly, blood is incredibly safe; and transfusion, despite all the things that can go wrong that I just detailed, transfusion is also incredibly safe.

If one looks at the Institute of Medicine report that talks about error in delivery of health care, transfusion is there but it's only a very small piece of the puzzle. We all would like to have that disappear entirely. But why is the public so worried about the safety of the blood supply?

Well, some psychologists have suggested that risks can be quantified on the basis of whether or not the risk is observable to the person exposed and whether or not it's controllable by the person exposed. That is, if a risk is unknown to the person exposed or can't be known at the time, when there's a delayed effect, you don't know if you've been exposed to radiation today, you'll only know if you have some effect many years later, and when the risk is new or poorly understood, this tends to heighten the concern about that risk.

Similarly, if the risk has fatal consequences, if its occurrence is inequitable--that is, someone doesn't, quote, deserve to have some bad outcome--and if it's involuntary--someone doesn't have a choice whether or not it occurs to them--the public is more concerned. And so those events that occur in the upper-right quadrant of this risk space are those that the public tends to be most concerned about and where there usually are calls for regulation or some other step to reduce the risk.

And guess where transfusion falls? Although it did not occur in this publication, did not show up in their analysis, but clearly all of these factors that the public would tend to associate with greater dread would apply to transfusion risk, particularly infectious transfusion risk.

There are also other risk multipliers that pertain to transfusion. There is a millennia-old mystique about blood as the source of all life. Obviously, if you have bad blood, that has great psychological ramifications. If you need transfusion, you are obviously ill. So the association there I think has a multiplying effect.

If you need transfusion, it is undoubtedly involuntary. We have stopped giving transfusions for general tonic effects.

And I think patients are also very concerned that they cannot control the source and, hence, the drive for directed donations, where patients feel that they are better selectors of safe donors than those of us who have made a career out of it.

Some other psychological factors to consider, and that is the human desire to avoid certain death. Let me share a couple slides reporting the result of a survey that was done with normal college students. They were given a hypothetical situation that they were shipwrecked on one side of an island, and they had to get to the other side of that island in order to be rescued. They had two paths that they could take. Both of them were infested with bees. Along one path, the bees were very active, and there was a 25-percent chance that the person traveling along that path would be stung. But the bees weren't very venomous, and there was only a 5-percent chance of a fatality if they were stung.

On the other path, the bees were nasty. Now, they're a little bit slower; only a 1-percent chance of being stung if you went along this path. But if you were stung, you were a goner, 100-percent fatality rate.

So the respondents in the survey were asked: Which path do you want to take? You have to get from your point of shipwreck to the point of rescue. Which path are you going to take?

Now, if you multiply the overall risk of mortality, taking one path versus the other, they really are the same. So mathematically it doesn't really make any difference which one you take. You have an equal chance of getting to the rescue point.

But by a two-thirds majority, people picked this path. They wanted to go along the path where the bees were a little bit more active and only a 5-percent fatality rate.

Okay. Now, another group of individuals was given essentially the same scenario, but the numbers were switched. And so along this path, you see there's a 25-percent fatality, and here there's only a 1-percent fatality. What happened? There was a flip. Two-thirds of the individuals now wanted to go on this path.

The conclusion of these researchers was that people try to avoid situations in which they know they are going to die. And, indeed, the background for this study was another survey, individuals asked: If you only had a choice between one vaccine, would you rather get a hepatitis B vaccine or an HIV vaccine? And the numbers they were using for the B analogy really come from the risk of infection and the risk of fatality after being exposed to HIV or HBV through a needlestick exposure. And you see by the same two-thirds majority people would rather get an HIV vaccine than an HBV vaccine if they only had a choice of one or the other. So, again, the same concept that they want to avoid those situations where there is at least the perception of a guaranteed fatality because of an event.

Another issue that plays in all this, I think, and it plays on our chances of applying what I would consider logic to some decisions about where we should be applying our resources, something that's come to be called "the rule of rescue." And it's often phrased that an intervention that prevents imminent death, even for a small number of persons, is more highly valued than one that extends longevity at some time in the future, even if the life-saving intervention improves the overall health of the population by a smaller total amount. In other words, the public will regard as more important saving the life of someone who's about to die right now than saving the life of a thousand people who might not die for ten years.

Contrast, for example, even in the era before September 11, 2001, how much time, effort, resources, and angst was directed toward preventing something going wrong on an airplane versus how much money the country is willing to put into childhood vaccines. Vaccination programs routinely are underfunded, and it's difficult to get as many resources directed toward vaccination as an intervention, even though ultimately we will save far more lives by doing that than worrying about someone doing something on an airplane.

This concept really got in the way of the State of Oregon attempting to use some decision analysis logic to use their Medicaid funds as far as they would go about a decade ago. The State of Oregon decided to allocate the Medicaid funds in their state according to the cost-effectiveness of different interventions. And if a particular Medicaid patient had an intervention that had good cost-effectiveness attached to it, then that intervention would be applied. And if the cost-effectiveness of the intervention was poor and it fell below a particular break point, then only palliative care would be offered.

The concept was that if you did a little for a large number of patients, you would get more benefit than doing a lot for a small number of patients. However, the system fell apart as soon as the first small child needed a liver transplant and wasn't going to get it because of this system. A small, cute kid's picture on the front page, and the system was quickly altered.

So in my perception, how does the public value risks and outcomes in transfusion or elsewhere? Well, certainly the public expects transfusion to be safe, if not entirely risk-free. People fear imminent death, and they want us to do things to prevent that, and identifiable at-risk patients attract sympathy.

So where do we stand with the different risks of transfusion? Well, I've listed them here in a two-column format, starting from the most common things to the least common things. Those in yellow are actually risks of fatality in terms of per million units. Let me just pull a couple out here and show it graphically.

Here shown graphically are the risks per million units for bacterial contamination, not fatalities but just contamination; delayed hemolytic transfusion reactions that we haven't talked about; transfusion-related acute lung injury; and mistransfusion.

Now, looking at fatalities, the scale has changed. You see TRALI; bacterial contamination causing a fatality; anaphylaxis, which can occur after transfusion; and acute hemolytic transfusion reactions.

Well, you know, we would like to have all these bars be at zero, but I would just like to point out that if you compare these risks of either occurrence or fatality against infectious disease risks, infectious disease risks really pale by comparison. These are--in summation, you stack them all up together, and they just equal the risk of dying due to transfusion-related acute lung injury. And yet where does the public spend most of its attention? And probably where do most regulators spend most of their attention? And where does most of our money go related to preventing these things, which are extremely uncommon?

Clearly, we have reached the flat point of the curve. We can utilize more resources in making transfusion, either the units or the process, safer. But what we want to do is spend this money wisely. If we spend more money, we want to get good benefit on it. We'd like to spend less money and get even more outcome, but that's not likely to happen. But we certainly don't want to spend more money and have a very flat-angled arrow. That is, we want to get something out of further investments.

So how can we compare some of these alternatives? Again, just to beat a horse which is rapidly becoming moribund, let me just compare three different interventions that we could take and what we could get out of it. Let's look at HIV transmission, bacterial contamination causing a fatality in a platelet transfusion, and mistransfusion causing a fatal hemolytic event--shown on the top line here, the approximately current risk in the United States per millions units.

Now, what could we do? Well, we could go from minipool to individual donation NAT. You've heard about that, and we know that Dr. Bianco wants to have automation for that.

[Laughter.]

DR. AuBUCHON: To prevent bacterial contamination in a platelet from causing a fatality, we could culture every unit or, obviously not as sensitive, we could observe just for lack of swirling in that unit, which usually disappears if a unit is bacterially contaminated. And to prevent mistransfusion from causing a fatal hemolytic outcome, we could use a barrier system, for example, to make sure that the right unit is going to the right patient.

If we did one of these interventions, what would be the outcome? Well, HIV transmission, with apologies to Mike Busch, who undoubtedly has more accurate numbers than I do, we might go from about 0.5 per million to something around 0.25 per million. We might halve the risk, so that's a 50-percent reduction. That sounds good. But there's about a 0.25 per million improvement in terms of reduction of fatality risk.

If we culture platelet units, we probably would reduce the risk to certainly less than 1 per million. If we observe for swirling, we would not reduce it as far as if we cultured, but there would be some reduction. And if we used a barrier system, we would reduce hemolytic transfusion reactions to probably less than 0.1 per million. And there would, of course, be a cost to each one of these.

Now, you could conduct a formal cost-effectiveness analysis, which lucky for you I have not done, comparing these. But clearly, you can see that you can do something here that cost nothing and reduced the risk by 50 percent or reduced the right by 3 to 4 per million. Or you can spend $15 or $20 and reduce it to far less. Or show it this way. Forget the money involved. This intervention improves transfusion safety by 0.25 deaths per million. This intervention improves it by 7 per million, this by 4, this by 1. These are much larger numbers than this number by at least a factor of 4.

Well, what have we spent the afternoon talking about? We've been talking about this, which is not inappropriate. We all would like to reduce the HIV transmission risk. But we could get a lot more benefit by paying attention to some other things.

So, in conclusion, I would like to emphasize, as we are hearing more and more frequently in transfusion medicine circles today, that transfusion is a process that certainly involves a unit that is as safe as possible. But there is a process involved that needs to be accomplished carefully and accurately every time. And until we work our way through this process to identify how we can prevent patient and sample mislabelings and recipient misidentifications and failure to detect bacterially contaminated units from occurring, we will not make the transfusion event as safe as it possibly can be.

We need to focus on the risks that are the largest risks, not necessarily the ones that attract the attention of the New York Times. So we need to focus on the largest risks and look for systematic solutions in order to make transfusion as safe as possible.

Thank you very much.

DR. BRECHER: Thank you, Jim.

Comments? Questions? Celso, do you want to ask him about automation?

[Laughter.]

DR. BIANCO: Well, I wish automation could solve this one. But, Jim, I'm sorry you were not here in the morning, but we had a very interesting ethical discussion. But I think that the contradictions are in your superb presentation. And how do you deal with public perception and what the public wants in a democratic society, and what you as the expert--that was our great discussion--without being paternalistic think is the right thing to do?

DR. AuBUCHON: We do live in a democracy, and the public ultimately gets to call the shots. He who pays the piper gets to call the tune. And I think it is appropriate when the will of the public is expressed, either through Congress or through regulatory agencies, that push us in one direction or another. We as technocrats may not always like the direction that we're pushed, but we certainly do need to pay attention to that.

However, I think it is appropriate and really required of us as individuals who are aware of all of the details of the system to take whatever pulpits are available to share with the public what the real risks are. I mean, I'm very happy that this committee is addressing this subject, and I would hope that we would hear more testimony about this on Capitol Hill and in other places as well.

It may actually take transfusionists saying something that they don't like to do, which is standing up and saying that transfusion isn't safe, or pointing out new risks that the public doesn't know about rather than just saying you don't need to worry about HIV anymore and then sitting back down. Although the public is worried about HIV or West Nile virus, we may have to occasionally stand up and say in public or to a newspaper reporter, "That's not what we should be worrying about, and we're killing in patients in other ways that we could address and we should address."

Hopefully, through that kind of discussion we can garner support. Support may mean Medicare funding, but support for other steps that can be taken beyond testing for the latest virus to make the blood transfusion process safer.

DR. BRECHER: Lola?

DR. LOPES: It seems to me that it is unnecessary to stress the low prevalence of HIV transmission. The very fact that the prevalence has dropped is testimony to the fact that there were things that could be done that were done and are now making a huge difference.

If the public doesn't know--and I think you're quite correct that the public probably doesn't know how frequently errors do occur and how frequently contamination occurs--perhaps they do need to know. What I don't understand is, it took an awful lot of money, an awful lot of research to get where we are with reducing HIV transmission risks. Why is it so impossible to, with much less effort, reduce mislabeling, reduce the human error that causes the problems?

I just don't see the need to, in essence, criticize a technological solution to a technological problem while seeming to say if we just spent that money on labeling somehow the human error would disappear. I would be a little skeptical myself that there it's a technology/money issue.

DR. AuBUCHON: Well, there are a number of factors involved, and other blood bankers around the table may want to offer opinions. I think part of the problem, part of the reason that some of these solutions have not been implemented are represented by people like me who have not seen the light or just have not felt compelled--or pushed--to take the steps that are necessary.

For example, the study from Hopkins that I showed data from indicated that if there is any error in the labeling of the sample, whether it's just a date is missing off the sample or whether there's just a small error in the spelling of the patient's name--if there's any label error at all, there is a four-fold increase in the chance that that blood didn't come from the patient whose name is on the tube. And, therefore, it pays, in my opinion, to have a very strict policy that if everything isn't right on the label, the sample goes in the trash can, and then you call the floor and say, "Try again."

But it's difficult, admittedly, to deal with an upset surgeon or a nurse who then has to go back and perform a phlebotomy, which may have been difficult in the first place, on possibly a little infant or an uncooperative adult patient. It's just much easier to roll over and say, okay, we'll take the sample. But yet that's setting up the first step along a chain that may have a disaster at the outcome.

The steps that many blood centers and hospitals are now moving toward in this country is toward culturing of platelets in order to detect bacterial contamination where possible. Long ago some European colleagues got the idea first, and I'm very grateful that they did. And some of us on this side of the ocean said we can do that, too. Is it expensive? Yes, it costs money. Not huge amounts. Less than nucleic acid testing, but it does cost some money. Do we have to work out new systems? Do we have to figure out new logistics? Yes, we do, but it can be done.

With HIV there was public push to do something, and blood bankers did something. But in some of these other issues, because they are not immediately apparent to blood bankers or because not every blood banker sees one of these events in his or her career, there just isn't the same motivation to get up off the dime and do something.

DR. GOMPERTS: Mark?

DR. BRECHER: Ed?

DR. GOMPERTS: Jim, thank you for the presentation. I enjoyed it, as usual. Do you think there's a bit of a distortion by just focusing on HIV? Because the reality is if there's a new technology such as, let's say, NAT testing, the technology's applied not just to HIV but HPV, HCV, and perhaps West Nile virus. And under those circumstances, don't you think it would be more appropriate to look at the technology and what it brings?

DR. AuBUCHON: Oh, absolutely. And I was very pleased to see how quickly the manufacturers were moving to develop and apparently being successful in developing mechanisms to test for newly recognized risk using nucleic acid testing approaches. That was one of the hoped-for benefits of implementing this technology, that all you would have to do, quote-unquote, is drop in a new primer and you would be able to look for a new pathogen. And although I recognize that doing this in nine months is a huge undertaking--I don't mean to minimize that--it certainly is easier than trying to create an antibody-based test in that same time period.

So I'm all for looking at new potential for technology, but I just wish that the same kind of focus were placed on preventing mistransfusion. You know, the FDA did not say within nine months we want to make sure that no one is getting the wrong unit of blood in this country. They said in the nine months we want to make sure no one's getting West Nile virus, and that's important. But there are other things out there that are a much bigger risk.

DR. BRECHER: Keith?

DR. HOOTS: Again, very well stated, Jim. I wonder--it kind of harkens back to some of the psychological paradigms you were posing about the bees and stuff. But is that analogous to think that part of it is one is fixable as a fix; in other words, you can implement--use technology to fix it. Another may require a behavioral change, which is much more difficult for everyone, I think, in concept.

For example, highway deaths went up acutely when Firestone made defective tires. There was an immediate response. Immediately, people quite buying Ford Expo's because they didn't like Firestone tires. So there was a--the impact was immediate and the turn-around was quick.

By contrast, people probably down deep really do realize that talking on a cell phone while you're driving is not too smart a thing, and there's data now to support the fact that it increases fatalities.

But we don't seem to respond to that in the same way we did to Firestone, and I think the kind of fight that we're fighting here may be a systemic problem as much as it is anything else with the way we approach risk. I don't know. Just a--

DR. AuBUCHON: Well, I will admit to having driven while talking on a cell phone. But, of course, I was in control and I knew that I wouldn't have an accident while talking on a cell phone; whereas, if I'm going to have a transfusion and the blood center selects a donor that I don't know, well, maybe they didn't do it right. And I think that relates to the patient's desire to select their own donors, which has never been shown to provide a safer transfusion, yet people feel much more comfortable when they know that it's Uncle Harry who gave the unit of blood that they're about to get. So I think that relates to controllability of the event.

DR. KUHN: Jim, I want to compliment you on that presentation. I really enjoyed it. I think I enjoyed seeing those statistics and seeing the comparisons of the avoidance of certain deaths or death due to transfusions and bacterial infections in comparison with HIV, hepatitis. And I think that as I looked at and listened to what you were presenting, it makes perfect sense of how we need to develop new perceptions as we forge into the future.

I only would have to say that as a person who deals with psychology and also love history, I think we have to look to--we dealt with and reviewed a little bit this morning about the Institute of Medicine and understanding how that all came about. And I think that history has influenced our society. We saw a catastrophic incident that happened in the early '80s which took everybody by surprise. I think there was, as the Institute of Medicine report said, there was--I'm not sure if you want to say a failure, but there wasn't the due diligence given to be vigilant over what was taking place. And I think that there is a perception now that history still lingers there, and people are kind of lacking that trust or probably trying to re-establish that trust right now as we go on.

And I think there still is, due to that history, a fear of imminent death, but when you start to see statistics, it starts to make you feel a little better about how you are looking at the reality of things.

But I think it also comes across as we need to do more education of the public. I was thinking if this presentation was put in USA Today and we were flying on the plane traveling here, I think not only would it have caught the attention of the United States but also the media all around. They'd be looking at all these other causes of death, and probably HIV and hepatitis C would become pale in comparison.

DR. AuBUCHON: It's a double-edged sword. On the one hand, I would not want to attract attention to my field or to myself personally, having to ask pointed questions as to, you know, well, what is the risk and why haven't you done something about it. But, on the other hand, we may need some of that attention before we get enough propulsion and enough resources to address the problem. And perhaps this is something that this committee can do to benefit patients who are going to be receiving transfusions.

DR. PENNER: Jim, I also agree, very nice presentation. And just like yourself, none of these things ever happened in my hospital, so I don't know really what you're talking about.

[Laughter.]

DR. PENNER: And it really comes down to this is the perception that most of us have because it always remains an undercurrent that never reaches perception in the hospital, and I suspect the same thing at your hospitals. The medical staff has no concept that something of this sort happening has occurred, an error and sort of mismanagement. And that always is kept kind of low key because the administration is really not very interested in seeing this sort of thing rise to the surface.

Perhaps the real issue there is a matter of being able to publicize the situations. We went through--I'm remembering a very similar reaction when I went to a small hospital, and they presented a pulmonary embolism occurrence, fatal ones in relation to total hip and total knee operations. And all of the surgeons who were sitting there said, "Never have seen this." And they presented five deaths that year as a result of--and at that point, they said, "Oh, yeah, I remember that one."

So it's a matter of trying to keep it out of your mind, but I think we have to be able to bring it up on a hospital-by-hospital basis.

DR. BRECHER: All right. Thank you, Jim. Another excellent presentation.

To the committee members, I think we have a choice. The hour is late. We had a discussion planned for the end of today. However, we did move one of the talks from tomorrow into today. I think we could either briefly talk perhaps about smallpox, and I talked to Eve Slater over lunch, and what she really wants from us is just to begin a discussion and not really do anything definitive about smallpox. And perhaps we could bring this back at the next meeting.

Why don't we just defer all discussion until tomorrow. We have half a day, essentially, to do discussions. That would be my preference. Who wants to defer discussions until tomorrow? Who wants to begin today?

That's pretty evenly split. The Chair decides tomorrow.

[Laughter.]

DR. BRECHER: Okay. We're going to start at 8:30, if not a few minutes before 8:30. So be forewarned.

[Whereupon, at 4:38 p.m., the meeting was adjourned, to reconvene at 8:30 a.m., Friday, January 24, 2003.]

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