Blood Safety Transcripts

ADVISORY COMMITTEE ON BLOOD SAFETY AND AVAILABILITY

Sixteenth Meeting

WHAT LESSONS CAN BE LEARNED FROM THE EVENTS
OF SEPTEMBER 11, 2001, THAT WOULD STRENGTHEN THE SAFETY
AND AVAILABILITY OF
THE UNITED STATES BLOOD SUPPLY?

Volume II

8:02 a.m.

Friday, February 1, 2002

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

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

Voting Members

Mark Brecher, M.D., Chairman

Larry Allen

Celso Bianco, M.D.

Rajen Dalal, MBA

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.

Karen Shoos Lipton, J.D.

Lola Lopes, Ph.D.

Gargi Pahuja

John Penner, M.D.

Mark Skinner, J.D.

Jerry Winkelstein, M.D.

Government Representatives [Non-voting]

Mary Chamberland, M.D.

Jay Epstein, M.D.

Colonel G. Michael Fitzpatrick

Harvey Klein, M.D.

David Snyder, D.D.S.

Consultants to the Committee [Non-voting]

Christopher Healey, J.D.

Allan S. Ross

C O N T E N T S

AGENDA and ITEM

FDA Perspective on Disaster Preparedness
in Relation to Blood Products
Dr. Richard Lewis
Food and Drug Administration

Potential Biological Threats to the Blood Supply
Dr. Edward Tabor
Food and Drug Administration

Development of Products to Counter Biologic
Threats to the Blood Supply
Dr. Mark Weinstein
Food and Drug Administration

Public Communication on Blood Issues
During a Disaster

Public Comment

Committee Discussion and Recommendations

Adjourn

P R O C E E D I N G S

DR. BRECHER: Welcome to the second day of this Blood Safety and Availability Advisory Committee meeting. Our first session is going to be presentations from the FDA and the FDA perspective. The first speaker will be Dr. Richard Lewis on the FDA perspective on disaster preparedness in relationship to blood products, and we will stay on time today.

DR. LEWIS: Good morning. Thank you, Mr. Chairman, Dr. Nightingale, I appreciate the invitation to address the committee, members of the committee. Thank you.

Last summer, late in the summer, in August, the Office of Blood began efforts to coordinate our efforts to address bioterrorism issues, in part, to best utilize resources because HHS has recognized that bioterrorism is an important activity or countering bioterrorism, and the events of September the 11th and subsequently the anthrax attacks in October heightened or focused our efforts a lot more on not only bioterrorism, but terrorism in general. So we've tried to coordinate throughout the Office of Blood what we can do to address this particular concern.

In looking at what we do and how we do it, as it applies to terrorism, we saw four different areas of effort. We hope to protect the blood supply, we hope to assure, in what way we can, that there is a continued supply of blood. Because we have therapeutic products, we want to take actions to assure that individuals are treated appropriately where our products can be of use.

And in recognizing that everything that we do depends on the industry, both the blood industry and the pharmaceutical industry, we need to interact with that industry.

These particular areas of focus very closely parallel the activities of the Divisions in the Office of Blood, and thus the division directors in our office and their divisions have taken the lead. On actions to protect the blood supply, our Division of Emerging Transfusion- Transmitted Diseases, with the leadership of Dr. Heron Makasi [ph], is taking the lead on this; to assure continued supply, the Division of Blood Applications, with Dr. Alan Williams; actions to treat affected individuals, our Division of Hematology, with the leadership of Dr. Mark Weinstein; and then outreach activities, we've assigned that to the immediate Office of the Director, and Dr. Ed Tabor, the associate director for Medical Affairs in the Office of Blood is taking the lead on that.

Dr. Tabor will address the committee later on this morning on another component of his activities; that is, emerging infectious diseases, but it's a component of his activities because of his interactions on emerging infectious diseases with the PHS working group.

This is what I was just describing. Each of the divisions is assigned a lead, and our counterterrorism efforts reflect those initiatives.

In actions to protect the blood supply, the Division of Emerging Transfusion-Transmitted Diseases has a number of functions. They are a research division, and thus their research is an important component of what they do. They also have responsibility for policy and regulation.

Dr. Makasi is not on the program this morning. Let me just comment briefly on those actions, and you will hear from some of the leaders later on this morning.

The research that FDA CBER does has a number of objectives. We hope to develop a new understanding in various methods of testing, to develop our own expertise in evaluating industry-submitted methods that we have to review for safety and efficacy. There have been a number of initiatives that have been completed in that division that have been transferred to industry for further development, and the Division of Emerging Transfusion-Transmitted Diseases has a large part in lot release testing for blood-screening test kits.

Some of the research that is ongoing there now that is rapidly under development includes microarray technology, as well as nucleic acid testing. In terms of pathogen removal and activation, there is a collaboration between the Division of Emerging Transfusion-Transmitted Diseases and the Division of Hematology, pathogen activation and removal with respect to both blood and blood products, as well as plasma derivatives, and the Division of Hematology has ongoing efforts in filtration methods, chemical and activation methods.

In terms of policy and regulation, we have a large part of our policy development in donor screening and suitability has to do with infectious agents. The expertise, again, lies in this division, as well as emergency release of blood components, and as I mentioned, product release and possible exemptions for product release.

I should say we heard a number of speakers yesterday comment on the lot release program at CBER. As you know, the biotechnology products are exempt from lot release, and there are mechanisms where industry products can be exempt from lot release, given that the particular manufacturer has a good record for their particular product in meeting their release specifications, as well as an overall good compliance record.

In the next category, actions to assure continued supply, we see the development of emergency response procedures as an important component. In part, again, speakers yesterday pointed out how our imagination is an important component of our response. And in identifying possible attack scenarios, we think that that is an important part of our imagination, trying to think like the enemy, to identify the way they may attack us. And the types of attacks that we're considering in developing our strategies include biological, chemical and nuclear attacks, and then to look at different ways that we might respond to attacks of various sizes.

We also heard yesterday from a number of speakers that evaluating the particular effect of an attack immediately, as well as the blood needs, is an important component. The people in the Division of Blood Applications are looking at various ways that one might be able to evaluate immediately short-term needs for blood as well as long-term needs.

We also heard how the blood that is on the shelves is an important part of our immediate response, and determining how much blood needs to be at a particular place at any one time is an important component of having a prepared response, and not only the blood, but test kits and other blood collection supplies.

You will hear more later from Dr. Weinstein about actions to treat affected individuals, but to help give you an overall framework of our plan, part of their work has to do with developing consistent advice and reviewer guidance for sponsors who may be developing investigational products.

We've recognized that immune globulin might be an important therapy in an anthrax attack, and the Division of Hematology has been coordinating with both CDC and the DOD in what it may take to develop such a product.

Also, in the event that there may be multiple types of products, licensed, as well as investigational, human derived versus animal derived immune globulins or plasma products, there needs to be strategies for prioritization, that is, which product would be used first and for which particular demographic.

And then another important component is the safety of these particular products in an emergency situation. We don't want to look at use of a particular product in retrospect and recognize that it was only used because of the immediacy of the situation, without giving it adequate safety evaluation.

I mentioned immune globulins for anthrax. There is a licensed product for botulism toxin. There was licensed products for the therapy of vaccinia, but we recognize, and I think Dr. Weinstein or some of his division will speak later about immune globulin for vaccinia in the event that there are efforts for smallpox vaccination nationally.

I mentioned previously, by way of introduction, to evaluate various inactivation methods for manufactured products. We heard yesterday from Chris Healey that it is important to the plasma industry and the plasma derivative industry to ensure that no particular bioterrorist agents contaminate their particular product. So inactivation for manufactured products are the first line of defense, one of the first lines of defense, rapid testing and release of licensed products in the event of an attack, as well as what we can do to assist in the evaluation of current supplies and possible useful products.

Finally, in our outreach activities, Dr. Tabor is leading our efforts in this, and we recognize the need to interact with blood organizations to develop emergency procedures. In fact, we have a number of representatives on the AABB Task Force that we heard from yesterday. We hope to interact with reagent and supply manufacturers in evaluating their particular reserves, as well as their strategic depots of product throughout the country.

We have seen, in a number of instances, that the interactions with other government agencies are important. We are interacting not only within CBER because the Office of Therapeutics and the Office of Vaccines have important strategies and plans are being developed so that there is a coordinated CBER effort, as well as a coordinated FDA effort, and we also recognize the need as both an HHS agency, as a federal agency, the need to interact with other groups there.

We also heard about transportation and how important transportation is, especially in the hours immediately following attack, and we recognize the need to be able to move both reagents and supplies, as well as samples. Our history tells us that sample movement was also a concern.

This is the overview of our plan. We hope that it is a coordinated plan. We would appreciate the comments of the committee, as well as the public this morning, and you will hear some more detail about the different aspects of this later on. You heard some of that yesterday from Dr. Williams as well.

Thank you.

[Applause.]

DR. BRECHER: Thank you, Dr. Lewis.

We have time for a few comments and questions.

[No response.]

DR. BRECHER: If not, we'll move on to the next speaker, Dr. Ed Tabor, on potential biologic threats to the blood supply.

DR. TABOR: Good morning. An important part of the Food and Drug Administration's response to the increased risk of a bioterrorist attack on the United States and the impact that such an attack might have on the blood supply has been the creation of a list of potential agents and their characteristics. This list can be used to guide research and policy decisions to enhance our preparedness should such an attack occur.

The FDA list is titled, "Infectious Agents Potentially Transmitted by a Transfusion of Blood Products with a Potential for use in Bioterrorism." A copy of this list was on the table outside the conference room yesterday. And, unfortunately, due to apparently a misunderstand, the list that was distributed to you is not, in fact, the most up-to-date version of the list and perhaps, if you're interested in the few changes that have occurred since that copy, just ask Dr. Nightingale, and he'll get it to you.

This list grew out of an earlier list of agents. For the past four and a half years, the U.S. Public Health Service Committee on Emerging Infectious Diseases, a working group that reports to the Interagency Working Group on Blood Safety and Availability, has met regularly to evaluate new developments in infectious diseases that might signal the emergence of any new threat to the blood supply.

The committee maintains a database of known emerging infectious agents with the potential to enter the blood supply. Most agents on that list were those whose pathogenicity was known and whose transmissibility by blood was considered to be possible. A copy of that list was also provided to the committee.

The Centers for Disease Control maintain another third list. This is a publicly available list of infectious and chemical agents that could be used by terrorists. This list can be seen at their website, www.bt.cdc.gov. Using the CDC list as a basis, we determined which of the agents on the CDC list could present a risk to the safety of the blood supply.

In general, this meant identifying agents on the CDC list that have an asymptomatic incubation period, during which someone might inadvertently donate blood. In practice, it meant comparing the CDC bioterrorism list with the PHS Emerging Infectious Diseases list for blood.

In the event of a bioterrorist attack, if infections caused by the attack remained asymptomatic for days or weeks, blood donations during that period could be infectious, and new infections could be transmitted by transfusion and be unrecognized for a period of time. Even after a bioterrorist attack had been recognized, it might be difficult to maintain an adequate blood supply if asymptomatic infected potential donors could not be easily separated from uninfected, healthy donors.

Clinical data are sparse for many of the agents on the list, so we've had to rely on expert advice rather than published studies in some situations. Much of that advice was obtained from various U.S. government agencies, including the CDC and the Department of Defense, and we are very grateful to all of those who took the time to answer our questions about the agents.

I will now present a brief summary of the characteristics of the agents on the FDA list. I want to emphasize that I am not an expert on any of these agents and that the purpose of this presentation is to provide an overview for you.

This information about the agents should provide a framework for discussion about measures that can be taken to anticipate potential bioterrorist threats to the blood supply. We need to consider potential strategies and how those strategies can be implemented efficiently. However, those strategies are beyond the scope of my present talk.

The CDC list is part of the CDC's strategic plan for biological and chemical terrorism, and the full website where the list can be seen is shown here on this slide. The agents on the CDC list are divided into Categories A, B, and C.

Category A organisms are those which are easily disseminated or are easily transmitted from person to person. They are organisms for which there is a high mortality, and they are organisms that cause diseases with the potential to cause panic in the general population.

Category B organisms are those that are less easily disseminated and have a somewhat lower mortality.

Category C organisms are in some ways nearly as important as Category A organisms. These are emerging agents that have the potential to cause the same kinds of problems that Category A agents have.

For the FDA list, we have designated each agent as being Priority 1, 2 or 3. Priority 1 are those agents that have an asymptomatic viremic or bacteremic phase, and this, of course, usually during the incubation period.

Priority 2 agents are those that may have an asymptomatic viremic or bacteremic phase, but there is either inadequate data or no data available, and Priority 3 agents are those for which there appears not to be viremia or bacteremia during an asymptomatic period, but they are agents that are transmissible by blood and appear on the two lists that I mentioned earlier.

The first and perhaps the most serious agent on this list is the agent of smallpox, variola major. As I'm sure most of you know, the last case of smallpox anywhere in the world was in 1977, and since that time the agent has been stored, perhaps somewhat naively, in only two locations--the former Soviet Union and the United States.

Our feeling, our false feeling of security with regard to smallpox, can be illustrated by two quotes from the leading virology text, the two-volume Fields Virology, and I've got those on this slide for you to see.

First of all, Fields Virology begins the smallpox section saying because smallpox is not extinct, we use the past tense in describing it. And later in the section, in the section dealing with the clinical manifestations of the disease--this is the latest edition of Fields Virology, it says, "There is little point in delineating the clinical features of this now extinct disease."

I think this illustrates some of the pitfalls in reviving lost information about an agent that was thought to be extinct.

Smallpox is Category A, Priority 1. It's an orthopox virus, a double-stranded DNA virus. Transmission is usually by oropharyngeal secretions. Now, even though the virus is present in smallpox scabs, and that formed the basis for the practice of variolation in the years before the development of a smallpox vaccination by Jenner, in actual fact, transmission by scabs is less common.

The incubation period is generally up to 12 days, and during those 12 days, there's a 2- to 4-day period viremia is present with no symptoms, and I will discuss that in a little more detail in a few minutes.

The main symptom is a rash. Death occurs in 20- to 50-percent of susceptible individuals, and death can precede the appearance of a rash. The agent is resistant to drying for very long periods of time, months at room temperature. It consists, in any one infected individual, of both enveloped and nonenveloped viruses. Both are infectious. Most of the virus particles are nonenveloped, and this could theoretically cause problems in our hopes to inactivate this in plasma derivatives if it were to enter the blood supply.

Now, as I mentioned, asymptomatic viremic smallpox can occur during the incubation period in individuals who have never been infected before. Asymptomatic smallpox can also occur in those individuals, some individuals who were previously vaccinated or were previously infected and have imperfect immunity.

There was a report in an article in 1971 that describes the detection of inapparent smallpox infections in 27 percent of contacts of new cases based on the detection of high-antibody titers. I'd like to say that I am indebted to Celso Bianco for directing me to some sources of early articles on smallpox, and if Celso will forgive me, I'd like to mention that during his medical training, he served on a ward that had 200 smallpox cases.

There is also a syndrome that occurs in small numbers of individuals infected with the smallpox virus called variola sine eruptione. These individuals have either pharyngitis and fever or conjunctivitis and no rash, and smallpox virus has been isolated from the pharynx and conjunctivia of these individuals, and I think it's safe to assume that their blood would probably also be infectious.

I'd like to just mention a corollary of concern about the smallpox virus, and that has to do with concern about the impact of vaccination against smallpox on the safety of the blood supply. There are a number of questions that come to mind, and I don't propose to answer them in this talk, but I'd like to call them to your attention.

One question is are potential donors who were vaccinated before we stopped vaccinating in 1971 in this country fully immune in some cases to smallpox or are they only partially immune and will they have the presence of vaccinia virus in their blood for some period of time or are they not immune at all to smallpox and what will be the impact of that on the blood supply?

And then, in addition, we need to ask the question will individuals who are vaccinated have a viremic period with vaccinia that will have an impact on the safety of blood that they might donate.

Another agent on the list is the agent of Rocky Mountain Spotted Fever, Rickettsia Rickettsii. This has no category. It does not appear on a CDC list, but we have designated it as Priority 1. It's a coccobacillus, with no specific gram-stain characteristics. Under natural conditions, it's transmitted by the dog tick in the Eastern and far-Western United States and by the wood tick in the Rocky Mountain regions. There is one reported case of transmission of this disease by blood transfusion.

It has an incubation period of 2 to 14 days and asymptomatic infections do occur. The symptoms are fever, rash, shock, seizures and coma, and death occurs in 3 percent of treated individuals.

Filo viruses, Marburg virus and Ebola virus are Category A, Priority 2. These are single-stranded, negative sense RNA viruses. They are transmitted by oropharyngeal secretions. This has been seen in experimental transmissions between monkeys and in transmissions to humans in the nosocomial setting. These have also been transmitted by needle stick.

The incubation period is 2 to 19 days, and there is no data available on whether viremia is present while the patient is asymptomatic. The symptoms are fever, nausea vomiting and diarrhea, wasting, and ultimately bleeding and coma, and death occurs in between 20 to 90 percent of individuals.

Yersinia pestis is the cause of plague. This is Category A, Priority 2. This agent is a gram-negative bacillus. It has an incubation period of 2 to 4 days. Yersinia pestis causes a zoonotic infection. Humans are only accidental hosts, the normal host being rats, and it's usually transmitted, under natural circumstances, from rodents to humans by fleas. Human-to-human contact spread does occur during epidemics.

The statement on the slide is incorrect. It's actually in epidemics transmitted from human-to-human by the pulmonary route. Death occurs in 8 percent of individuals, even with treatment. The death rate can be as high as 33 percent, individuals who have septicemia.

There are three major clinical forms of plague. Bubonic plague is characterized by fever and enlarged, painful lymph nodes called bubos, hence the name bubonic plague. The patients develop hypotension, shock and purpura, and the purpura gives it it's moniker, "Black Death."

The "Black Death" was the cause of about 40 million deaths in the 1,300 throughout Asia and Europe, and this included one-third of the population of Europe.

Another clinical form is a septicemic form. This is characterized by a fatal bacteremia and hypotension without bubos.

And, finally, the pneumonic form, the most contagious form of plague, occurs when the organism spreads to the lungs from the bubos. It's highly contagious and is spread by the pulmonary route to other exposed persons. It's always fatal if antibiotics are not given within 24 hours.

Tularemia, caused by Francisella tularensis, is Category A, Priority 2. This is a gram-negative coccobacillus. Under natural conditions, it's transmitted by ticks and by contact with infected mice, squirrels, beaver and rabbits. Occasionally, infections occur in hunters who handle infected animals. It can also be transmitted by food or water that is infected by such animals, and it can be transmitted by aerosol.

The incubation period ranges from 1 to 21 days, and it is not known whether bacteremia is present during an asymptomatic period. The primary symptoms are fever, lymph node enlargement and skin ulcers, and death occurs in 4 to 6 percent, even among treated individuals.

Typhus caused by Rickettsia prowazekii is not on the CDC list so it does not have a category, but we designated it Priority 2. This is caused by a coccobacillus, and it is normally transmitted by body louse or by contact with flying squirrels, in some cases. The incubation period is 6 to 15 days. It is not known whether bacteremia is present during an asymptomatic period. Symptoms include fever, rash, and central nervous system symptoms, including confusion, and death occurs in 3 to 4 percent of infected individuals and at a higher rate in individuals over age 60.

Q fever caused by coxiella burnetti is Category B, Priority 2. This is a gram-negative coccobacillus. It's transmitted by aerosols from infected farm animals. The incubation period is not known, and it is believed, although there is no data, it's believed that bacteremia during an asymptomatic period is possible. It causes pneumonia, endocarditis, hepatitis and central nervous system symptoms, and death occurs in 2 percent of treated individuals.

Crimean Congo hemorrhagic fever virus is Category C, Priority 2. This is a member of the Bunyaviridae family. It's transmitted under natural circumstances by ticks from carcasses of farm animals, contact with their blood or with the carcasses. Nosocomial transmission is occurred by blood and person-to-person spread can occur by aerosol. The incubation period is 1 to 9 days when transmitted by ticks, and from 5 to 13 days when transmitted by blood.

It is not known whether there is a viremic period in the absence of symptoms. The symptoms of this infection are shock, disseminated intravascular coagulation, bleeding thrombocytopenia, and death occurs in 10 to 50 percent of individuals.

The Hantaviruses cause two different syndromes. The Hantaan strain and Seoul strain of the Hantaviruses cause something called a hemorrhagic fever with renal syndrome. These agents are Category C, Priority 2.

The virus is normally transmitted by aerosols of rodent urine. In the case of these virus strains, it's urine of the striped field mouse and other species. The incubation period ranges from 4 to 42 days, and it appears that there are probably some individuals who are viremic in the absence of symptoms.

The symptoms of this syndrome are fever, thrombocytopenia, and nephritis. Death occurs in 1 to 15 percent of individuals and chronic renal insufficiency occurs in many of the survivors.

Other strains of Hantaviruses cause the Hantavirus pulmonary syndrome. These viruses are in Category C and Priority 2. They include the Sin Nombre and Andes strains. These are normally transmitted by aerosols of urine from the deer mouse. The incubation periods range from 9 to 33 days, and it is likely that there is a viremic period in the absence of symptoms. The symptoms of this syndrome include fever, shock, and pulmonary edema, and death occurs in 30 to 40 percent of individuals.

Finally, the tick-borne encephalitis viruses that appear as Category C on the CDC list are Priority 3. These probably include Colorado tick fever, which represents a disease caused by seven different Coltiviruses, members of the Reoviridae family. The incubation periods range from 5 to 15 days. The symptoms are meningitis and encephalitis, and death occurs in 2 to 22 percent of individuals.

This provides you with a summary of the agents on the list that we have prepared, and it should form the basis for future discussions today and in the future.

Thank you.

[Applause.]

DR. BRECHER: Thank you. We have time for some questions/comments.

Dr. Popovsky?

DR. POPOVSKY: Dr. Tabor, do your contingency planning include one of the two possible scenarios, other than the threat of actual infectivity of a unit of blood from an asymptomatic donor, that if terrorists struck a particular metropolitan area, thus, potentially exposing thousands, if not millions, of people, that then you would have to deal with one of two possibilities; one, deferrals, red blood donor referrals that would have an impact on the productivity, as it were, of blood donors for that area; or, B, that if, and I think we might hear some of that in the next presentation, we use immune globulins or other agents to defend against it, that that could cause reactivity in test results as we've seen with the influenza vaccine some years back with HTLV testing?

DR. TABOR: Well, I think this, like many things in the bioterrorism area, this is a moving target. First of all, I think the greatest immediate concern would be if donors donated and their blood entered the blood supply before we were aware of a terrorist attack, that would be our most immediate concern, and then, of course, if there were a terrorist attack, maintaining a blood supply thereafter.

If you had infections with agents for which we had no screening test, which probably would be the case, you would have to exclude large numbers of potential donors simply because of their geographic location.

DR. POPOVSKY: Right.

DR. TABOR: And you'd have a challenge in maintaining the blood supply in a metropolitan area where perhaps everybody was excluded as a donor.

And then if the attack were with an agent for which we have let's say a globulin that will be described in one of the talks later this morning, we would have to make determinations as to whether people who had received those globulins should be deferred and for how long.

But it's also a moving target because research is underway to develop screening methods to detect some of these agents in the blood setting, and I think once you have a screening--if you have the ability to screen, and I don't think that's something you're going to see in the very short term, but we might see it in the foreseeable future, that would change the regulatory picture also.

DR. POPOVSKY: Thank you.

DR. BRECHER: Celso?

DR. BIANCO: You gave a very nice summary, Ed, and I was looking at our package, and even if I don't have the right table, it's a very nice table of agents.

One observation is that there is only one Category 1, that is, smallpox, that would be the most concerning and devastating. There are other things that I think would be very interesting if they were added to the table.

The first one I think is this table actually should be widely distributed among our community so that people know a lot about it more than they do. But one thing is would those agents be inactivated by any of the plasma methods that are currently used to treat plasma derivatives, and the second one, if they partition, if they are predominantly cell associated or plasma associated, because certain products could be available still with a lower risk and others wouldn't.

I, also, think that this would encourage the people that are working with methods to inactivate infectious agents even in cellular products, to try to test their systems and see how those agents would be treated.

DR. TABOR: Those are very good suggestions, and we'll follow up on that.

Thank you.

DR. BRECHER: Rick?

DR. DAVEY: Ed, a very nice presentation.

A couple of questions about smallpox. Is the Agency aware of studies underway or are you considering studies to look at the extent and the robustness of the population's immune status with smallpox because that would--

DR. TABOR: You are referring to populations who are previously vaccinated.

DR. DAVEY: Yes.

DR. TABOR: Let me give a short answer, and then I think I'll ask one of the other people from the Office of Blood to add onto it. I know that, from discussions I've heard at NIH, that there are groups in NIID that are looking at that, and I don't know what stage those studies have reached, but I would say I first heard of them two or three months ago. So, as you are probably aware, there are ongoing vaccination programs.

I think it should be possible to look at levels of antibody in people who had been vaccinated, say, between 1940 and 1970, and also to look at the antibody response in people who are revaccinated. I wonder if, Dr. Scott, could you or Dr. Golding answer that further? Can you say something about studies that are ongoing to look at the duration of immunity in people who are vaccinated against smallpox in the past?

DR. SCOTT: I just arrived, so I missed the original question.

DR. TABOR: I'm sorry. I didn't mean to catch you off guard.

The question was are there studies ongoing to look at the duration of immunity to smallpox, which effectively means looking at vaccinia titers, antivaccinia titers, in individuals who were vaccinated in the distant past?

DR. SCOTT: Right. Our understanding is that, historically, antibody immunity can last for up to 30 to 40 years, but it isn't predictable in any one individual whether this may be the case.

I am not aware of current papers which have published data about the level of immunity, but I do know that this is being looked at by various groups. We also think that licensed immune globulins, which are not specific immune globulins, have some antivaccinia titers, which indicate that some members of the population do have antibodies.

DR. HOOTS: Can I follow that up?

DR. BRECHER: Keith?

DR. HOOTS: What about cellular immunity? Have people looked at, I mean, we know that in hepatitis B, for instance, you can over the years lose your humeral, at least detectable humeral, immunity and still have very good cellular immunity and be relatively resistant, if not completely resistant to reinfection?

Has anybody looked at specific smallpox antigen response to ex vivo T-cell responses like is done with HIV and hep B and that sort of thing?

DR. SCOTT: I attended a CDC meeting last March, and this was part of the topic, and there are some members of industry and academia who are looking at this, although the assays for cellular immunity in vitro haven't been well developed. But another thing suggests that some cellular immunity exists, and that is that some people with low antibody titers still don't have a very good response to the vaccine when they're revaccinated, suggesting that they have active cellular immunity.

DR. BRECHER: Ron?

DR. GILCHER: Mike, my question relates to a different virus, one that's very common, hepatitis A.

My question is this: Bioterrorism doesn't necessarily have to kill. All it has to do is create tremendous fear, anxiety, disrupt everything we do. Hepatitis A is easily spread. On the other hand, it's very easy to vaccinate, as far as numbers of people, which we're doing in the U.S. Have you considered hepatitis A as a potential bioterrorism virus and, if not, why?

DR. TABOR: We haven't. Let me start out by saying I feel that the whole topic and the list are dynamic, and we welcome suggestions. Sometimes it takes a new view to be able to see something that one wishes one saw beforehand.

I think in the case of hepatitis A, the risk to the supply of blood for transfusion would probably be quite low because the period of infectivity for hepatitis A is really, well, it's short, but I guess it does occur before symptoms appear, so there could be a period when people would donate. It's worth considering.

DR. GILCHER: I have done two studies in my life, one at the University of Pittsburgh, about 25/28 years ago, and one when I came to Oklahoma, where I looked at 2,000 blood donors who said I have never had hepatitis. So they had passed the screening.

Of interest, one-third of those individuals in Pittsburgh, now this is almost 30 years ago, had anti-HAV, and in Oklahoma about 28 percent, one out of four, had anti-HAV. So these are old studies, but it showed how common the infection was.

The point is that I think we've been protected in the past by the fact that so many people have had subclinical infections, and that may even true today, but I don't know. But it does get into the blood supply, in rare instances, and would pose a threat, and it would potentially remove large numbers of potential donors. That's my concern, and we would take out huge numbers of donors. They would be deferred for six months to a year, depending on what criteria we would put in at that point.

DR. TABOR: Well, in fact, if there were--the suggestion about hepatitis A is a good one, and we'll consider that. I don't think it would cause a problem for up to a year, however.

In the American population, I think the prevalence of antibody to hepatitis A is probably, in young adults, somewhere around 20 percent and substantially higher in middle age and older adults. But the infectivity period for hepatitis A virus ranges from 2 weeks before the onset of symptoms until very slightly after the onset of symptoms.

So, once we were aware of a bioterrorist attack with hepatitis A, it would be something that we could deal with, I think, quite easily, and really the risk would be before we were aware that we had, for instance, that the water supply of a major metropolitan area had been contaminated or something like that, but hepatitis A is a good suggestion, and we'll consider that.

DR. BRECHER: Ed, following up on what Ron said; you know, the goal often is to create terror. Has the FDA taken any specific actions to try to prevent sabotage of pharmaceuticals or blood bank manufacturers or even thought along those lines? I mean, I would think someone could come in and spray bacteria at some stage of processing after the QC that would have major ramifications.

DR. TABOR: If it's all right with you, I'd like to refer that question to someone else, if I could.

Dr. Epstein, could you try to answer that?

DR. EPSTEIN: We have certainly thought about sabotage, and it would include chemical, as well as biological threats. I would just have to say that thinking about response plans is just at a very primitive stage. Likewise, the whole issue of dealing with mass disruption of the donor base, thinking is at an early stage.

So, you know, we're aware that these concerns are part of the spectrum. It's just that we're trying to focus here and now on identifying the biological agents of concern, and we are going to have to deal with these other concerns.

DR. BRECHER: Question from the audience? Please identify yourself.

MS. KHABBAZ: I'm Rima Khabbaz from the CDC.

I just wanted to mention, if people are interested, there is a recent, the February issue of the Emerging Infectious Diseases Journal has an article that outlines the criteria and rationale for the Category A, B, C lists for Bt agents that Ed mentioned, and these categories, these lists, are not meant to be extensive or all agents that could be used for Bt, but, really, the division by category is to guide public health preparedness, and I would refer you to that article to clarify how the process took place.

DR. TABOR: Yes, that article is actually very good and provides an historical perspective on the development of that list.

DR. BRECHER: Celso?

DR. BIANCO: I think that we can think a lot, but what I think very valuable from the CDC criteria and in the way this has been done, is that gives a set of priorities; thinking that a terrorist or whoever wants to have impact, which ones would have the biggest impact and which ones we would be forced to address. We can't do focus groups with the terrorists to see--

[Laughter.]

DR. BIANCO: So, in a certain way, I think that the most important thing is to prioritize and to see where we put our initial effort.

DR. TABOR: I think, similarly, you may want to think about putting a priority, in terms of ease of manufacturing. Some of these organisms are much easier to grow than others.

DR. HEALEY: As I mentioned yesterday, at least at the fractionation facilities, they do have emergence response plans in place for what might be considered anticipated events, such as a fire or a HAZMAT spill, things like that.

I can also tell you that, post-September 11th, security at the facilities has been on heightened stage of alert for most of these facilities. Most of them are secure facilities, to begin with; you know, pass card entry and so forth and so on. But through our working groups, we are looking at sabotage and things like that, so it's something that is on the table.

DR. BRECHER: Okay. If there are no more questions or comments, we'll move on to our third speaker, Dr. Mark Weinstein, talking about development of products to counter biologic threats to the blood supply.

DR. WEINSTEIN: It will take a few minutes to boot up the computer.

[Pause.]

DR. PENNER: I'd like to add a comment while we're waiting, and it's already been brought up, but from the committee's viewpoint, we'd really like to know which of these agents are going to be susceptible to withstanding what is normally used as protective measures for blood and blood products. How many of them can withstand the cold for two weeks or a month? How many of them can withstand heat, detergent, et cetera? So if that information was suggested, I think it would be very important if we could get it.

DR. WEINSTEIN: We'll be addressing some of those issues as we go along in this discussion.

Dr. Lewis has already given you an overview of the Office of Blood's strategic plan to counter terrorism. Part of that plan is to help in the development of biological products to treat individuals who have been infected by certain pathogenic agents that might be used as terrorist weapons.

The focus of today's discussion will be about our efforts to address the threat posed by Category A infectious agents that have been identified by the Centers for Disease Control and Prevention.

I will talk in general terms about our overall strategy, after which my colleagues at the FDA will speak more specifically about our progress in developing hyperimmune globulin products directed against anthrax, botulinum, and vaccinia.

One of the first things that we did to develop our strategic plans was to form small working groups within the Office of Blood to evaluate each of these agents identified as potential threats.

These working groups interacted with other groups within CBER, with our sister agencies in the Department of Health and Human Services, and with the Department of Defense to form interagency working groups. I'd like to emphasize how good these interactions have been and how necessary they are to really develop a comprehensive plan to address these agents, potential pathogenic agents and threats.

One of our objectives was to identify those pathogens in Category A that might be amenable to treatment with biological products, particularly immune globulins. At present, we are focusing on anthrax, botulism and vaccinia. However, potentially, immune globulin products could also be developed against plague and hemorrhagic fever viruses such as lassa, Argentine and Marburg viruses. It is unlikely that an immune globulin product will be effective against tularemia. We are also interested in developing immune globulin products directed against other infectious agents, not on the A list, but these efforts are of lower priority at present.

We assessed the potential of hyperimmune globulin therapy to be effective against the three pathogens. In the case of botulism, high titer immune globulins from human and animal sources are considered effective. Vaccinia immune globulin is thought to be effective against certain complications of smallpox vaccination. In both cases, however, our conclusions are based on small, uncontrolled studies. Less is known about the effectiveness of immune globulin therapy against anthrax. The less that is known, the more work that has to be done by way of preclinical and clinical trials to establish the safety and efficacy of the product.

To help us focus and prioritize our efforts, we estimated how much product is currently available and the potential need in the future. The latter calculation was based on estimating the number of individuals likely to be affected, the effective dose, the amount of material presently available, and the presence of supportive care.

From this assessment, we can estimate how much high titer immune globulin needs to be made. In all cases, it is clear it would be beneficial to have larger amounts of hyperimmune globulin products than we have currently available. To produce these products in large quantities, we will need a scale of manufacture several orders of magnitude larger than any done in the past.

Polyclonal immune globulins can be derived from human or animal sources. Before these products can be prepared in large quantities, high titer human plasma might be useful as potential therapy in some situations; for example, a treatment for anthrax, where no manufactured product is now available.

Another source of therapy that bears consideration is that from immune globulin products that contain high titers of vaccinia immune globulin. They might prove useful as an interim measure before large amounts of the hyperimmune product can be developed. We are actively considering this, but this is not the focus of today's discussion.

To obtain potential sources of hyperimmune globulin, the Office of Vaccines at CBER, the NIH, and the DOD have helped to identify vacinees as potential plasma donors. Once identified, efforts will be needed to recruit these vacinees for plasma donation. For the manufacture of plasma derivatives, plasma must be collected under specified screening and testing requirements for source or recovered plasma.

In some cases, particularly for botulinum immune globulin, it is unlikely that large numbers of human donors will be available. It may be necessary to rely on animal sources to prepare large amounts of this product. FDA has helped to clarify what are the requirements to collect plasma from each of these sources.

Finally, the large-scale manufacture of these products is dependent on obtaining a sponsor who may or may not be the manufacturer and a suitable manufacturing facility. FDA has assisted CDC in identifying potential manufacturers of immune globulin products so that CDC could make decisions about whom they might want to approach. The pool of vacinees is limited, so it is important that there be a coordinated effort to use this resource most efficiently. Another issue that must be resolved is who is to pay for the development and manufacture of these products.

The Office of Blood is heavily engaged in helping to design criteria for the licensure of these products and in evaluating preclinical and clinical protocols.

In some cases, there are no recognized surrogate markers for clinical efficacy.

Given the current state of knowledge, some products may be licensed on the basis of PK, and safety results by surrogate markers for efficacy will be obtained in post-marketing studies. Today you will hear about our current thinking regarding the clinical development of the VIG.

The Office of Blood is involved in the development of new potency assays. Research work is required to establish which of these assays will be predictive of clinical utility. We are also developing new potency working and reference standards for some of these products. These standards are essential as references to establish potency of new manufactured products.

Now, there are a number of unresolved issues. One is the funding for development and manufacture of new products. The manufacture of large amounts of products that we hope will never have to be used does not seem to be commercially viable. Decisions have to be made about who is to fund and what is to be funded. This issue of funding is part of the problem of coordination and prioritization. Potential products have been identified, and as you will hear, a great amount of preparatory work has been done already on the feasibility of large-scale manufacture. But we have to decide which, if any, of these products are to be manufactured.

If these products are developed, decisions will have to be made about how they will be distributed, who will distribute them, and who will receive them.

I would now like to introduce my colleagues, who will tell you in more detail about our plans to develop these products. Dr. Golding from the FDA will talk about the development of botulinum and anthrax immunoglobulin products from the perspective of the FDA.

Nina Marano from the CDC was expected to talk about their plans to develop anthrax immunoglobulin, but she is stuck in Atlanta. However, Dr. Golding has reviewed her slides, and we will see whether he can carry it off and tell you about what she had intended.

Finally, Dr. Scott from the FDA will speak about our plans for a vaccinia immunoglobulin.

Thank you.

DR. GOLDING: Good morning. I'll be talking about the FDA role in botulism and anthrax immunoglobulin preparation.

As you probably know, Clostridium botulinum is a gram-positive bacillus, and it makes an exotoxin, in other words, secreted toxin, and that there are eight different strains. And, unfortunately, these eight different strains are non-cross-reactive, so an antibody against one strain does not neutralize the other strains. So you have to make antibodies against all strains.

The toxins can be aerosolized and used as biological weapons. The toxins act by binding to nerve endings and interfering with nerve impulse transmission to muscles resulting in paralysis. This is a very distressing condition because the victim cannot talk, cannot breathe, and is in very dire straits unless the victim is helped. And the treatment consists of respiratory support and antitoxins.

We did this back in '96 and we did in again September 11th and we did it again recently for the Winter Olympics. We assessed what are the current supplies, and we do this on a routine basis in the Office of Blood. And there is one licensed product made from horses in limited amounts, and there are some IND products made by various sponsors, mainly the Department of Defense, and these products are now available through agreements between the CDC and the DOD under INDs so that they will be accessible should there be any biological threat with botulinum. And the DOD, in other words, has agreed to ship a large amount of its material to depots that will be accessible to the CDC in case of an attack.

So this has involved obviously all kinds of logistics and discussions between us, the CDC, Department of Defense, and including the NIH.

As I mentioned, an IND was drafted for the Olympic Games in '96, and this IND not only mentioned all the products that were available under licensed products and IND products, but also gave an algorithm, providing the algorithm for treatment. In other words, what do you start with first? What do we think is the most appropriate of the antitoxins to use first? And when that's used up, how do you go to the next product and so on?

It's clear that these products have a finite life, and we have to be interested in facilitating development of new products. And through our BOONS (?)--that's our computer system--we've been able to identify INDs that are actually regulated by the Office of Vaccines and communicated with them and identified groups of individuals that are being vaccinated with botulinum toxin and could be a potential source of new product. And we've entered into discussions regarding this with CDC, DOD, and NIH, and we are trying to encourage sponsorship--well, the FDA cannot sponsor the actual IND. It has to be a sister agency that sponsors the IND.

An important aspect that Dr. Weinstein already mentioned is to develop and validate the in-house standards and assays. Part of the problem is, because there isn't a lot of commercial interest in any of these products, that the government has to step in and provide the background for potency assays and to make sure that standards and assays are available. And a lot of work is being done in this respect by different agencies, including the FDA, and this is done mainly in the Office of Vaccines and Bacterial Products.

So this can be done by us or it can be done by other government agencies or by contractors to ensure that standards and validated assays are available.

So the current status of botulinum immunoglobulin, as I mentioned, there are licensed and IND products. The human licensed product is a relatively old product made in horses, and it is only active against three of the toxins: A, B, and E. The equine product that is available from the Department of Defense is a heptavalent product and is available against--and is potent against seven of the different toxins, and there are various human INDs that are pentavalent and are active against five of the toxins.

So we do have product available for any bioterrorist threat at this moment in time, but I think it's important to emphasize that for the future there needs to be some kind of plan to develop new products, one, because these products have a finite lifetime and, two, because we have--if we are in a situation where we're using up some these products, we need to have some kind of back-up in case of additional threats.

Moving to anthrax, bacillus anthracis is gram-positive. It can be aerosolized, as we found out recently, and used as a bioterrorist agent. Contact can cause cutaneous or skin anthrax, but the severe form of the disease is due to inhalation and various forms of pulmonary involvement, particularly hemorrhagic mediastinitis.

But, again, like botulinum, important in the pathogenesis are the release or secretion of exotoxins, and there are three actual proteins that are secreted by the bacillus that are critical. The protective antigen actually provides a docking space on the cells that binds to cells, forms a pore, and the other two toxins can then bind and gain entry to the cell and do their damage. So the other two toxins are named edema factor and lethal factor.

So treatment or prevention, I'd just remind you that in this last set of events where anthrax inhalation was occurring, five of the eleven patients with inhalational anthrax died, and that was despite intensive antibiotic therapy. So, clearly, antibiotics are important, but if we had other agents that were effective, we should try them, and immunoglobulin's obviously something that is worthwhile trying.

The other option, of course, is vaccines. This is the human vaccine called AVA. As you may have read from your newspaper this morning or heard yesterday, it has been released now and is again available. This is mainly against the protective antigen. The data that we've seen, multiple injections are required to get some kind of titer, and those titers follow very quickly after the last immunization. So the titers don't last for much longer than three to six months.

This is a treatment modality that's important, but, again, it's not optimal treatment for this condition. And that's why the equation of antibodies and immunoglobulin products was raised as a potential for treating anthrax.

The evidence for the antibody role is scanty. Experiments have been carried out in vitro showing toxin neutralization. Experiments have been done mainly in rodents showing protection, and this has been done to a large extent mainly with the horse serum or horse product and a very limited extent of any human serum or product.

So the possible clinical indications for antibody use would be inhalational anthrax not responding to antibiotics, but this could be expanded if we had enough product to consider post-exposure prophylaxis. If anthrax organism was used that was designed to be antibiotic resistant, as far as I know the only the Internet we have is to use antibodies, and then you would also maybe consider high-risk patients such as the elderly, immunosuppressed, diabetics, and so on.

So what have we done? We've identified vaccinees. This is obviously together with other agencies. Our first identification involved contacting the Office of Vaccines, speaking to the reviewers and then speaking to people in CDC, Department of Defense, and NIH. Independently of us, the CDC obviously had been thinking about this, and together with the CDC and other agencies, an IND was drafted by the CDC and submitted to us for advice, and this IND is expected to be submitted as a basis for use of human anthrax immunoglobulin for treatment of inhalation anthrax.

We also have research plans at the FDA to provide a basis for development of a sheep anthrax immunoglobulin.

And that plan, just a few points about that plan. We want to study different vaccines or immunogens in animals, and the advantage of using animals is that you can use the whole bacillus. There is an attenuated strain that is approved by the USDA for vaccination of animals, and this contains all three toxins and some other cellular components of the bacteria, and there is at least a theoretical possibility that using this antigen will give rise to more extensive antibody response that may be beneficial in treatment. So we'll chose the immunogen that elicits the highest titer and identify manufacturers or sponsors to make products in animals. We also need to facilitate preclinical testing in mice, rabbits, and possibly monkeys, and, very critical, we need to develop standards and assays. Some of these assays are already up and running in the Office of Vaccines, and we need to work with them in order to validate them and make them available for these products.

Again, with animal anthrax immunoglobulin, we need to facilitate IND submission and product approval.

I think I've covered this slide. So the assays that are available, there's an ELISA assay in laboratories at the NIH and FDA. There's the toxin neutralization assay that's available at CDC, USAMRIID, and at the Food and Drug Administration, and rodent testing available at CDC and USAMRIID. And there's potentially monkey testing in Rhesus macaques, and this would be the critical test for any product. But the problem is that there's a shortage of monkeys, and this is a bottleneck. So you're only going to do this testing when you have developed a product to a point where it's very close to human use, and this would be the final critical test of efficacy using monkeys and using inhalational anthrax as a challenge.

So the current status of the anthrax program, high-titer fresh frozen plasma units are available for inhalational anthrax and for production of a pilot lot of anthrax immunoglobulin, and there's a plan to test animals with human high-titer anthrax immunoglobulin. And there's a consensus of the anthrax immunoglobulin working group to plasmapherese vaccinees for manufacture of an anthrax immunoglobulin product.

I just wanted to give this slide--this pertains, I think, to all the products that we're talking about, and this is a hypothetical calculation. But it's just to give you some feel for how our thinking is--how we calculate the dosages and the needs in terms of actual human doses. So the variables, when you think about it, are the antibody titer in the product, the expected toxin level of viral or bacterial loads in the victim, and the relative affinities.

What I mean by that is the antibody will have a certain affinity for the toxin or the virus, but the toxin will have a certain affinity for a cell receptor. And you want to have an advantage with your antibody so its affinities are at least in the range of binding that would enable it to compete with the toxins binding to the receptor.

So rough estimates--and I've used as an example here anthrax immunoglobulin. If you consider a dose--and this is a ball park figure--of 100 milligrams per kilogram, and you're considering a 70-kilogram person, this is 7 grams of product. To obtain 7 grams of product, you would need two units of plasma; in other words, plasmapheresis of about 750, 800 ml. And the reason why you need two units is because during the manufacture you lose 50 percent of the immunoglobulin.

So if you had 100,000 victims of a particular attack, you would need to have started with 200,000 units of plasma to manufacture the product, and one way to do this is to have a donor pool in the range of, say, 20,000 and have plasmapheresed these donors ten times.

Now, this is eminently feasible because there are many more than 20,000 people out there in the military that have been vaccinated against anthrax. For this scenario, this would be a feasible project to pursue.

Acknowledgments. I couldn't fit everybody on one slide, so I'm going to start out by saying that the most important people are not here. The upper management of CBER--Jesse Goodman, who's in the audience, Jay Epstein, Mark Weinstein, Richard Lewis--have supported and directed this effort and made sure that we have kept our nose to the grindstone. But we have had considerable help from other people within the agency and in other agencies. So regarding the botulinum, in the FDA Marian Gruber and Cynthia Kleppinger are experts in this area and are reviewers of the INDs. Nisha Jain and Toby Silverman are in our division and are clinical reviewers and have helped prepare the data. In the CDC, we've had frequent contacts with John Beecher, Debbie Dodson, and I'm probably missing some names.

Regarding anthrax, again, in the FDA, Cynthia Kleppinger and Bruce Meade as the research basis and has been developing the assays, and Ross Pierce is a clinical reviewer that's worked extensively with the CDC in talking about the need--what is needed to be done in order to prepare an IND. And in the CDC, some of the people involved are Jai Liapapo and Nina Marano, who is going to give the next--was giving the next talk. And I guess I'm going to need help to find her talk.

Should I ask for questions?

[No response.]

DR. GOLDING: Actually, this is a test because I didn't actually plan it that way, but the ability of me to present Nina's talk would reflect on how good our communications have been and whether I really understand what they're doing.

This is going to be somewhat repetitive, but this is from the CDC perspective, the anthrax immunoglobulin for prophylaxis and treatment, an interagency product, the development plan, and she has CDC, NIH, DOD, and FDA is hidden somewhere down there.

Immunoglobulin as adjunctive therapy for inhalational anthrax. So the toxin plays a important role in the pathophysiology of acute inhalational anthrax disease. Recent anthrax bioterrorism events have shown that treatment with antibiotics alone is not fully effective, 45 percent case fatality rate, and immunoglobulin as an antitoxin is used for other toxin-mediated diseases such as botulism, tetanus. And I would add here that I think the same principles are involved in neutralizing a toxin as you would for neutralizing a drug. And as some of you may know, there are polyclonal immunoglobulin products licensed for treatment of the digoxin overdosage.

Anti-anthrax immunoglobulin equine is currently generated using live strain anthrax vaccine in Russia and China. We have tried to get data from those sources, but I haven't seen anything apart from verbal reports of efficacy.

Potential use for infection with antibiotic-resistant strains, and there's limited animal data, equine antisera in particular, on efficacy with no information on dose, timing, and potency. And what this points out is some of the work that we have to do, either in the FDA or other agencies. There's a lot of preclinical testing that needs to be done that would help in decisionmaking regarding treatment of patients.

Okay. What the CDC has been doing and the way I like to think about it is this is what they were doing pre-September 11th, starting out in March of 2001. They had an interagency agreement with USAMRIID and NIH to recruit and screen the AVA vaccinees. So these are military vaccinees receiving the human-licensed anthrax vaccine, and they were going to obtain anthrax immune plasma by plasmapheresis, and then they were going to use this to make reagents for quality control of serology assays, in other words, set up standards, and they would also use the IG preparation for animal studies of passive protection. So, in other words, they were going to make a product from some plasmapheresed military personnel and use that to make standards and use that to do preclinical testing.

So they collected 115 600 ml plasma units. They were collected at the NIH and stored at USAMRIID, and they were screened by an ELISA assay, which measures protective antigen, and you can see at the bottom of the slide the range was quite variable. The median was 277 micrograms per ml, which I would say, considering other hybrid immunoglobulins and other infections and toxins, is a very respectable titer. Obviously this is just a binding titer, and we don't know anything about functionality. But as binding titers go, this would compare favorably with other infectious states or other situations where you--or the type of antibody levels you would like in order to neutralize a toxin.

So in mid-October 2001--this is obviously post-September 11th--discussions were held with the CDC for possible uses of the anthrax immune plasma and anthrax immunoglobulin for treatment of future anthrax cases. So what happened, we said, okay, you know, now this is a real situation. We have anthrax cases. What do we have and how can we use it? And what they had was these plasmapheresed units, and the idea was to set aside some of those units for compassionate use and then to go on and to make a product with the remaining units.

October 26th, the FDA convened a multi-agency conference call chaired by Jesse Goodman, and December 7th, an IND protocol was submitted to CDC IRB. December 12th, the Department of Transfusion Medicine at the NIH submitted a protocol to their IRB for plasma collection from AVA vaccinees. And this was in order to allow collection of plasma and to prepare fresh frozen plasma for compassionate use, and, in addition, to use these units to prepare an anthrax immunoglobulin product.

So for these considerations for making the anthrax immunoglobulin intravenous product, the plan should ensure an adequate number of doses for civilian and military use. So this is several--on the order of several thousand treatment doses. And enough was prepared--you know, I would say this slightly differently. I mean, the immediate need, I think everybody would agree, is that you have material for patients who are dying because they're not responding to antibiotics. But in addition to that, you could consider adequate quantities for repeat dosing. You could consider adequate supply for post-exposure prophylaxis and treatment for antibiotic-resistant strains if this were to be found. And you would need full cooperation and enthusiasm of industrial partners for product expansion.

And as you go from bullet to bullet, I think you're increasing the total amount that you need by an order of magnitude, at least.

Okay. So the product development, and this Mark Weinstein said several times and is very critical to the success of this whole policy. We need to identify industry partners to process existing units to AIG, and the GMP material has to be used for preclinical animal testing and manufacturer must be capable of appropriate product characterization, and CDC bioassays and reagents should be available for technology transfer.

The idea is that CDC or other government agencies would have standards and assays in place so if a manufacturer was identified and funding was available, they could go ahead and make the product, and they wouldn't have to spend a down period developing assays, that these assays would be made available by government agencies. And we need to establish a continuity of supply of at least 500 to 1,000 liters.

So what is in progress is collaboration with USAMRIID, NIH, and a commercial plasmapheresis partner, and the idea is to perform GMP fractionation to AIG IV for animal and human clinical studies, and maintenance of some of this material as a reference standard.

So the product that is made, according to GMP, ideally would be used for the preclinical animal testing. If you make something offline and it's not under GMP and you do preclinical testing, it's somewhat problematic to the FDA. So it is important, if possible, to do the preclinical animal testing with a product that is made by a manufacturing scheme that can then be used to make subsequent products. This preclinical animal testing would be in small animals, rabbits, and rodents, and we've mentioned the monkey model, which is really inhalational anthrax. And human testing would be used to determine safety, tolerability, dose ranging, and PK, pharmacokinetic studies. And based on these results, you could make recommendations hopefully about dosing, and this would probably be the basis for licensure.

So the goal is to obtain a larger lot of plasma for manufacture, a donor pool. These could be donors from U.S. military bases. There are many, many thousands of soldiers out there that have been vaccinated and have a high titer. The military vaccinees, they know already on the basis of studies that have been completed that they need at least four doses of the current vaccine and a booster within 12 months to have reasonably high titers. And in order to do this in an efficient way, you need to use a commercial plasmapheresis facility, and you need an industrial partner who is in from Ground Zero, I would say, to develop this product and that has the infrastructure to do this in an efficient manner.

So what is required? Extensive interagency interaction and collaboration, expert preclinical and animal studies, expert laboratory support for testing of pilot efficacy, an experienced industry partner, coordinated, ethical IRB review process, intensive partnership with the FDA, dedication of adequate personnel and funding, and the funding should be underlined three times.

Acknowledgments. These are Nina's acknowledgments: Jai Lingapapo, who's at the CDC and prepared the IND; Bradley Perkins, who's at the CDC; Dave Stephens at the CDC; Conrad Quinn at CDC. So all these people are involved with anthrax. Phillip Pittman, who's actually in charge of the IND trials for the anthrax vaccinees; Susan Leitman, who's at the NIH, the Director of the Transfusion Service; Chris Ockenhouse, who's an M.D. at Walter Reed, who has come up with a development plan in parallel, and a lot of his points are now being taken into consideration; Robert Gasser, also at Walter Reed. The rest of the players I think you know: Mark Weinstein, Jay Epstein, myself and Jesse, all from the FDA.

Thank you for your attention. If there are any questions?

[Applause.]

DR. BRECHER: We have time for some questions. Keith?

DR. HOOTS: It seems like what we've heard a lot of are the types of bioterrorism that one would traditionally think of as state-sponsored or device-delivered, the sort of thing that militaries would have developed over time for that use, insidiously, perhaps. How much thought--I'm sure a lot of thought has--but we just haven't heard anything about it today, and I just thought I would ask. In terms of the blood supply, there's another way to think of things--getting back to what Ron's point was--in terms of terror, you know, there's the type of terror we've all felt after September 11th, which is acute. But if you think about how it came to be, it actually was very insidious because all the processes that allowed that to come to be took two or three years underground to develop. So obviously time is not an issue, really, when you're thinking about it. It's more how do you get the most impact and how could you possibly deliver things insidiously so that you actually build terrorism over time.

If you were going to do that, one of the ways, it seems to me, is if you had an agent, probably some sort of infectious agent, that was easily delivered internally, that would then become, you know, incorporated, you know, and then perhaps be transmitted by blood down the road in its resting phase, what kind of--you know, I mean, obviously that's almost impossible to answer. I understand that. But I raise it because those--you know, we're talking about PPTA and all the stringencies that have gone into trying to protect their plasma. But if you were going to do something very insidiously and you chose a product that was widely available, table salt, table sugar, something like that that you could get into, you know, how those kinds of things--are they on the table for discussion as far as how to prevent that kind of thing from happening?

DR. GOLDING: Well, you know, I think you're opening up the discussion to a very wide area, and, you know, table salt, for example, I don't know what the Center for Foods is doing to protect foods. There obviously have been attacks where people have sprayed salmonella on salads and stuff and things like that. So I don't think I'm in a position to answer that question.

I think that for the most part what we're talking about here are agents that could be treated by antibodies, and that's what we've focused on. It may be, again, regarding a previous question, that, you know, what we've done is focused on the Category A agents, and even there we're narrowing it down to anthrax, smallpox, and botulism. So we are narrowing our focus, and maybe that is a mistake. But I think that if there were evidence in the literature, first of all, that these threats are potential and real and that antibodies would be protective, I think that would--any area like that we should look into. So we should keep our eyes open and try and be aware of other threats, and if you can make antibodies against it, we should think about that seriously.

DR. BRECHER: Chris?

MR. HEALEY: This isn't focused on the bioterrorism point, but it does go to the issue of blood and plasma availability and terrorism along those lines. Has the agency looked at all the suppliers of materials that go into, you know, blood and plasma production, particularly where there may be sole suppliers or relatively few suppliers, and trying to assure that stockpiles are--those supplies are available in the event that there was some action against one of those?

DR. GOLDING: I'm trying to understand your question. You're saying that this is not necessarily to treat bioterrorist agents. You're saying, just to give an example, there's a hyper-immunoglobulin against hepatitis B and somebody targets that manufacturer because it's--and there's a limited supply and that's what caused the problem. Is that your question?

MR. HEALEY: Actually, no. My question is more along the lines of if--and this is completely hypothetical. If, for example, there were a sole supplier of a certain type of glass used for vials for products, has the agency looked at those types of components to assure that if one of those suppliers were suddenly unavailable, that there may be alternative sources available?

DR. GOLDING: I think I'll defer that to Jay.

DR. EPSTEIN: Why do I always get the hard questions?

Well, I think the way I look at it is that we're at war, that what we're talking about is part of homeland defense, and that the effort has to be an all-court press; and that we are here, at least in part, to get the best possible perspective on what concerns we should be focusing on.

Now, having said that, we can only be where we are, and we have finite resources. And there's a need, at least at this stage of the effort, to have very clearly focused priorities. And where we have gone first is to focus on what appear to be the leading threats.

That's not to say that we will disregard or can afford to disregard other potential threats. But if the committee or other organizing groups, you know, within government or the private sector, have a different perspective on where the priorities ought to be at this stage or as we go along, we certainly have an open mind because, you know, the goal is to address all threats. It's just that we cannot do everything at once.

MS. LIPTON: Jay, I agree with you. I think that Chris' point, though, is something that we were looking at yesterday, and that is, that in the long term you need to build redundancy into the system. And, you know, we are in a very peculiar environment, I think, in blood banking and transfusion medicine, where, instead of seeing people coming into the field and developing multiple suppliers, we're seeing a consolidation, I think primarily related to economic issues. So you're right, it's nothing we can focus on right now, but the same way we worry about building in redundant capabilities, you know, to respond to disaster, we ought to be thinking about that.

DR. BRECHER: Let me just say one thing, Jay, then you can go ahead. I think the sense of what we've heard this morning is that the blood supply is a secondary target, where the perception is that it would not be a primary target of a terrorist act.

However, I could see that if somehow they contaminated 50 units around the country, the tenuous confidence that the blood community has built with the public would be shattered, and no one would want a blood transfusion all of a sudden. And so it is, I think a potential primary target, and we need to at least think along those lines as well.

Jay?

DR. EPSTEIN: I couldn't agree more, Mark, and you just have to remember cyanide in Chilean grapes to realize what kind of panic can come from a minuscule outbreak.

But to Chris' point and Karen's comment, I quite agree that managing supply in the face of disruptions is one of the key objectives in counterterrorism planning. It's one of the things that Dr. Lewis highlighted. And I think that the entire set of presentations yesterday was meant to be eye-opening about what the issues are.

I would only say that we should not assume that every answer comes from government, and one of the issues that this committee is here to deliberate is the proper role of government versus private sector initiative. So I agree with you, Karen, and I'm glad as representative of AABB that it's you that said it, because I do think that the industry needs to examine how it is currently structured and how it currently functions in terms of becoming robust to threats, threats to the system. And that would include the spectrum of threats. You know, it would include outbreaks. It would include vaccinations. It would include, you know, physical disasters. And it would include tampering and sabotage. It's all of the above.

DR. DAVEY: Along those lines of preparedness, we focused on blood and donors and the public. I'd like to put on the table the impact on the staff of our facilities itself. In New York City, you know we had not only the Twin Towers disasters, but then the anthrax consideration both here in Washington and New York. We had blood drives at NBC when those letters were discovered. We had a blood drive at Governor Pataki's government building when that issue was discovered. We had a death of a person who worked two blocks from our blood center. And our staff was understandably very, very concerned about the potential impact of this threat on them, on their personal health.

So I think in my experience, I found very quickly that I had to become an expert on anthrax and cutaneous anthrax--and I must say I haven't seen a lot of cases in my life. But I do want to thank the CDC for getting the material together very quickly that helped. A number of employees came to me with skin lesions. You had to know a little bit on what to tell them, and it was a little rough.

Our mailroom people were especially concerned about handling bulk mail. We took a couple steps. We moved all activities that weren't related to mail out of that area, like copying machines, et cetera. We put in HEPA filters so that big mailbags could be opened in a negative pressure atmosphere. Again, that was along with some CDC recommendations. Whether this was too much or too little, we don't know. But it certainly was something we could do for our staff to reassure them that we cared and there was somebody, some leadership at the blood center that had their interests in mind.

We also let the staff know very carefully that we had very clear links with CDC and our local public health authorities so that if additional threats, whether anthrax or something else, occurred, that they had someone on board who was looking out for their interests.

I think the point I'm trying to make is our staff can be very concerned, disrupted, distracted, and may not even come to work at times of biological threats like this. And that in itself can be a very significant threat to the blood supply.

DR. BRECHER: Okay. Last comment, Dr. Popovsky?

DR. POPOVSKY: Thank you, Mark.

Something you said a moment ago, Mark, dealing with the potential ramifications of an infection, or two or three, of contaminated units on recipients, conversely the same could be said about the fear that could be spread through misinformation to blood donors. We dealt with the HIV fear, tangible, unquantified, but very real, in the blood banking community for 15 years. And I can envision that through scientific illiteracy and misunderstanding, a case that would be widely reported in the press could somehow be translated that it would be a personal risk for a blood donor to come in. And I think we should consider that in our contingency planning, how we will deal with the donor education side of bioterrorism. It just occurred to me, as you were speaking.

DR. BRECHER: All right. Dr. Scott, you're on.

DR. SCOTT: Now we're going to switch from bacterial threats to a viral threat, and so I'm going to talk about the FDA role in counterterrorism with regard to the use of vaccinia immunoglobulins to treat adverse events after smallpox vaccination.

First, I'd like to give you just a small amount of background. I think many members are already familiar with the facts. The smallpox vaccine is a live-virus vaccine. The organism is vaccinia, and, in particular, this vaccinia strain is called Dryvax. It's an attenuated New York City Board of Health strain.

Routine vaccinations in the U.S. stopped in 1971, and this was after a risk/benefit assessment where it was believed that the risk of deaths from continuing smallpox vaccination was greater than the risk of deaths from smallpox itself in the U.S.

The last case of smallpox occurred in Somalia in 1977. Other routine vaccinations were stopped in the U.S. subsequent to that of health care workers in 1976, actually, of travelers routinely in 1982, and of the U.S. military, we understand, in 1990. So the only people who are routinely vaccinated anymore are laboratory workers who are working with certain strains of pox viruses. You can find this information on the CDC website.

I'm listing here the complications of smallpox vaccination, and the ones in bolded yellow are the ones that are considered to be treatable with vaccinia immunoglobulin, which I'm going to refer to as VIG, V-I-G, but VIG technically is for the IM preparation. There's also an IV preparation, VIGIV.

The first of these is eczema vaccinatum, and that is a disseminated viral infection on the skin of people who have eczema, whether or not the eczema itself was active at the time of vaccination, or in some cases in people with other exfoliative skin disorders, and the case fatality rate in the literature has been reported to be 10 to 80 percent prior to the use of vaccinia immunoglobulin. Now the case fatality rate after VIG is thought to be about 1 to 6 percent.

Progressive vaccinia, also known as vaccinia necrosum or gangrenosum, is necrosis in the area of vaccination, and this just continued to necrose, to take over whole limbs. Usually there are metastatic lesions. And this was always fatal prior to the advent of VIG treatment. Now the case fatality rate after VIG--and this is based, of course, just on anecdotal reports--is thought to be somewhere in the range of 20 to 50 percent.

Ocular vaccinia, usually the accidental inoculation of the eye, is also VIG treatable, but I would point out that corneal infection is not.

Generalized vaccinia is a rash, usually in people without underlying illnesses. And I should go back to progressive vaccinia. That occurs in people with some kind of immunosuppression. But generalized vaccinia is typically mild. Perhaps in up to 10 percent of cases it's more severe, and the patient will look toxic. And treatment is usually not needed for these people to recover, and it's not a fatal reaction.

The other reactions that are not VIG treatable, these include skin hypersensitivity reactions and encephalitis.

There are two preparations of vaccinia immunoglobulins which currently exist. The first of these is VIG, the IM preparation, and this is available from the CDC under IND. It was made from source plasma from vaccinated military donors, and it was manufactured in 1994.

VIGIV is an IND product. It, of course, is an IV preparation. These studies are in progress, and it also made from source plasma from vaccinated military donors. The VIGIV was not made in 1994. It was made in 1999 and 2000, I believe, and it is still being made. But the source plasma from which it is made is the same source plasma as the VIG was made from. It was just frozen over all these years.

How much VIG might we need in the case of a smallpox attack? Well, this would depend upon the scenario, whether or not there was mass vaccination of the whole U.S. population, regardless of contraindications to vaccination such as eczema, or whether there was selective vaccination, meaning vaccination not of people who have immunosuppression or eczema or other conditions. And it may also mean selective vaccination only of smallpox, primary and secondary contacts. Obviously you need less VIG if you vaccinated fewer people under these conditions. And the question also arises the extent to which VIG might be used for prophylaxis. In the past it was used for people who were exposed to smallpox who had eczema as a prophylaxis against development of eczema vaccinatum, and it was believed to have worked at that time. It also may be used as prophylaxis if pregnant women need to be vaccinated.

Future production of more VIGIV depends on a number of things, and we are in the process of exploring all of these, as are some of our sister agencies. This would be identification, recruitment, and plasmapheresis of high-titer donors and/or immunization of new donors to make vaccinia immunoglobulin.

It also necessitates the identification of fractionators who are willing to produce this product. It also needs from our end an IND process for safety studies and assessments of potency.

Now, trials of vaccinia immunoglobulins are obviously complicated because we can't perform a clinical trial on affected individuals who are already suffering the side effects, the severe side effects of smallpox vaccination, because these are still relatively rare.

We also don't know from the past literature, which pretty much stops in the 1970s, what the effective serum titer would be for treatment of these vaccine complications. So this complicates the development of an efficacy study. So we need to determine what would be the optimal clinical study now for licensure since real treatment studies aren't possible.

We also need to figure out how to monitor the effects of treatment when people are treated, how to ascertain efficacy, and how to determine effective serum levels of antibodies for treatment. Right now we only have historical information, and we don't really have serum levels, we just know how much of a product was given and whether or not people got better, or the rate at which they got better.

We also need to assure adequate supplies of VIG or VIGIV for all the possible scenarios, and we need to assure delivery of this product where it's needed if we ever should need it.

I'm now going to present our current thinking about clinical trials for licensure of VIGIV. Licensure may be based on PK equivalence and safety data, and the PK would not be inferior to that of VIG given IM. Human surrogate markers, for example, the influence of VIGIV on vaccine take experimentally or lesion size, would not be required prior to approval because these are yet to be validated. However, I think these would be greatly encouraged.

An accelerated approval designation would be desirable, and this is described in 21 CFR 601.40, and I'm going to review that in more detail for you in a minute. This would expedite availability of licensed product, and this carries with it a commitment to Phase IV studies, which I'll go into right now.

The scope of accelerated approvals is for biological products that have been studied for their safety and effective in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefits over existing treatments. Incidentally, there's no licensed other existing treatment for complications of smallpox vaccine.

Approval may be granted on the basis of adequate and well-controlled clinical trials establishing that the product has an effect on a surrogate endpoint, and that's what we need to underline. And this effect needs to be reasonably likely, based on other information and evidence, to predict clinical benefit. And I think that's where we are with VIG and VIGIV. This is the kind of situation we find ourselves in where we only have surrogate markers to depend upon.

One of the most critical elements of an accelerated approval is that the applicant continues to study the product after licensure, and the purpose of this is to verify and describe the clinical benefit when there's uncertainty as to the relation of the surrogate endpoint to the clinical benefit. Post-marketing studies will be expected to be promptly underway, if not before approval. Such studies must be, and I quote from the CFR, "adequate and well-controlled and carried out with due diligence," and, of course, the product would still be subject to the same standard post-marketing recordkeeping and safety reporting as other biologics.

These commitments would no longer apply once FDA determined that post-marketing studies had indeed verified and described the product's clinical benefits.

So that was your CFR review. Now I'm going to continue on with the rest of our current thinking about clinical trials for licensure of VIGIV.

New product indications would be limited to treatment of VIG-treatable vaccinia vaccine complications, and the labeling would also be specific to the data provided by the manufacturer of each product. We would encourage the development of animal model studies. We would also encourage human surrogate efficacy studies.

I would like to point out that licensure in this case, the requirements may change as a result of animal and human studies and improved surrogate marker studies. Therefore, manufacturers even of approved products might have to update their data in accordance with new CBER standards, and lot release could be affected by failure to adhere to new standards. And by new standards, I am really speaking of standards for potency.

VIG potency assays face some challenges. I've listed here some of the potency assays that may be used, and currently the plaque reduction/neutralization assay is the one most commonly used, and it's sort of a modern version of what used to be used in the 1970s, which was a chick embryo pox model, where they looked at the ability of vaccinia immunoglobulin to prevent pox formation on these chick embryos.

Well, now this is much more conveniently done using plaque neutralization on susceptible cells with vaccinia.

The plaque reduction/neutralization assay has been developed by industry and is validated or nearly validated. There are also some academic institutions which have developed this, and we are also working on this within CBER, both in OBRR and OVRR.

In OVRR, there's a new neutralization assay which is being developed in Hannah Golding's lab. The advantage to this, the virus itself expresses a beta-galatocidase (ph) protein. The value of this assay is that it may be high throughput and actually a simpler assay to perform than the plaque reduction/neutralization.

The comet assay, which we are working on in CBER, beginning to work on, and is also somewhat developed elsewhere, detects ability to neutralize a form of virus that's important in in vivo spread. This form of the virus is not assayed for in these more conventional assays.

We're working on a mouse lethality model to look at potency in vivo at CBER, and there are other in vivo models that we're aware of that are being developed by industry, CDC, and others.

Well, if we're going to develop new potency assays and try to select the best or more relevant one for in vivo or actually for products, what we do need also is a standard. We have an anti-vaccinia antibody preparation which has been set aside for use as an interim standard, and this is being aliquotted and lyophilized at FDA. Distribution will be through CBER by request after potency is internally validated by the plaque reduction/neutralization assay, and we expect this will be available to anyone who asks in the near future.

This is some more of the ongoing research at CBER. We're developing and comparing in vitro and in vivo potency tests, and we are trying to assess these as relevant surrogate markers for treatment of vaccine complications. We're establishing the interim standard, as I mentioned. We're testing licensed immunoglobulin IV lots for the presence of anti-vaccinia antibodies. I alluded to this earlier, and we believe now that there are titers present in certain lots of licensed immunoglobulins, although, of course, they're not as high as what you see for the specific VIG and VIGIV.

We're also, of course, looking after the long-term evaluation of VIG and VIGIV stability and potency because these are preparations which may need to be used tomorrow or may need to be used in five years, and so we think it's important to make sure that we have a stable and consistently--persistently potent product.

Addressing VIG needs has involved a lot of cooperation and collaboration, and here I list some of the participants in these endeavors. The CDC has assisted us with the assessment of VIGIV needs under various scenarios for vaccination. The CDC, Department of Defense, and others have generated INDs and are planning to generate INDs for assessment of new products. And with NIH, we are coordinating to identify people who might be able to donate for plasmapheresis for a new specific immunoglobulin.

We're also collaborating with our sister office, OVRR, both on the vaccine INDs that they regulate and in the laboratory.

In addition, we are aware that both on the industry side and in academia there has been an effort and continues to be a good effort to develop and validate relevant potency assays.

So the current status, of course, as I've mentioned, is that VIG is available under IND for current vaccine complications; that there is good potential for new VIGIV products. We are studying the high anti-vaccinia titer lots of licensed IGIV to estimate their potential efficacy using various potency assays, and we are thinking about mechanisms for provision of high-titer lots of licensed IGIV in case of emergent need.

And, finally, I think we and everybody need to focus efforts on identifying the optimal surrogate markers for potency assays of these products.

Thank you for your attention.

[Applause.]

DR. BRECHER: Thank you, Dr. Scott.

We have time for maybe one comment or question.

[No response.]

DR. BRECHER: If not, we're going to take a break. We'll reconvene in half an hour at 10:40.

[Recess.]

DR. BRECHER: We're going to open this session on public communication on blood issues during a disaster with a statement from the government. Steve Nightingale has a brief statement to make.

DR. NIGHTINGALE: I can have stereo, but the people to which I want to address this statement aren't here yet. Could I move back from my role as speaker to my role as Executive Secretary and ask you all to come back to the table?

DR. BRECHER: Sit down.

[Laughter.]

DR. NIGHTINGALE: Your reservations are subject to cancellation.

All right. The last scheduled session before we go into public comment and committee discussion is a brief session, I hope, on public communication on blood issues during disaster. As you heard earlier this morning, the FDA has a four-pronged plan. The first three prongs I think are fairly straightforward, and they demonstrated that they were: protect the blood supply, assure continued supply and treat affected individuals, and then there was the broader segment of outreach activities, and there was understandably, I think, less of that because outreach activities is really an open-ended commitment. It is a commitment that we have made, but, nevertheless, it's a commitment that we need to get some input on, if not resolution for.

The private sector has also emphasized public communication as an essential component of their plans to manage an emergency. We realize that communications is essential. We probably think we know how to do it, but I haven't heard a whole lot of discussion about it. I've heard a lot more about anthrax immunoglobulin rather than communications specifically.

I, therefore, wanted to take about 20 minutes of this committee's meeting at the tail end to ask the members of the committee and to ask the public who is attending the committee with us to comment for the benefit of the government on how you think we could do better in the area of communications. This is neither an offensive nor a defensive question on our part. It's part of the statement of this whole committee process. We want to know if there are things that we can do better than we are doing right now to prepare for an emergency in the future.

The one comment that I want to put in as I ask you to prepare any comments that you would want to make to us is this: In January of 1998, at the third Advisory Committee meeting, the first one that I scheduled myself, I had invited Dr. Lola Lopes to come and talk to us on the subject of management of risk. Dr. Lopes talked a bit about distribution theory, and those of you who have not majored in that discipline probably don't remember everything she said, but I hope you remember something that she said at the tail end of the meeting, because I certainly do. She said that the public as a general rule is much more likely to trust an institution--to believe in an institution, public or private, in which it has trust. So I think that there are two related issues that I'd like to hear your comments on: What can we do, we as the government, to communicate with you better? And what can we do better than we are doing right now to earn your trust?

And with that, I know that Mr. Allen was here briefly and had to leave the meeting early. If I could ask the members of the committee as we go around the table if you have any thoughts on these to give us those, if any of the public has, and hopefully give us those by 11:05 so we can get on with the rest of the meeting.

Dr. Bianco, do you have any comments?

DR. BIANCO: Yes, I do, and this has been a superb meeting. I heard a lot of--even if all of us knew most of the things that were presented, we got a different sense, a more global sense, a more organized, integrated sense, and communications obviously was the one.

It made me also think a lot about what issues in communications we had, and there is one that was initially raised somewhat by Dr. Schmidt and Danny became part of it: the response of donors, for instance, that was one issue, to major disasters and their desires to contribute. I think--and trust, as you said, too.

I think that in part we in the blood community are responsible for some of that in the way we operate, in the fact that we always have shortages, the fact that we are always dealing with issues, and our marketing people that showed that people respond to disasters, people respond to appeals. If they are not too frequent, they come and donate blood.

And every ad that I have seen recruiting blood donors somewhere has an ambulance, a car accident, or something. So we have in a certain way placed in the minds of the public the fact that you donate blood when there is a disaster.

I don't see in the usual promotions that we make a cancer patient that is under chemotherapy receiving units of platelets several times a week that is dependent totally on those platelets, but as the subject of those things is more dramatic, because people respond to drama and that's what TV did to us, and to our children more than to us.

The other part that I think is important in the communication and trust, as you mentioned, is that we give donors continuously very conflicting messages. Since we are trying to serve a population of recipients, they are very sensitive to the messages of safety. And we have to take sometimes very draconian measures in terms of preserving that safety. If we look like we have now these CJD deferrals, that is, we don't--we are unable today to explain effectively to the donors and the public why we do it, why we are taking the measures, why so rigorous, why even the donor history is so complex and trying. That is, it is worse than the medical history that they have to give to their own physicians.

And so that in a certain way creates a sense of discomfort, and we have not learned yet on how to communicate that to the donors and explain these conflicting messages. You have these test that's positive that has no significance to your health, but you cannot donate blood. And the donor will tell you, If I can't donate blood, I'm not okay, what is wrong?

And deferrals are contagious, as contagious as smallpox, because a donor that is deferred, even for hemoglobin, a low hemoglobin, will go home and say, They told me that I'm not okay, and tells the friends, the husband, the wife, the children, and everybody then starts getting being afraid of going to donate blood.

And other things that we have not learned yet in terms of communication is how to maintain, sustain the blood supply with a cadre of people that feel that this is a civic duty to donate blood. It's not an emergency event. It is a civic duty.

So what the government can help us, and I think that this would fall in the purview of NIH and behavioral science and all that, I think that we did and we saw studies in the past like the Piliavin studies about altruism and why people donate. I think we have a different world in terms of media, in terms of communications, in terms of all the issues. I'd like to see these become a focus of an RFP, something that is really studied, because it's fundamental, blood donation is an issue of public health. And it's fundamental for us to maintain a population of donors that allows our health care to proceed.

DR. HAAS: I second all of that. I think the other problem is that we're a society of 30-second sound bites. That probably contributes to the very image that Celso was talking about.

I think the problem is that the benefit of blood to society in general is an abstraction that's hard to put some concrete picture to, but I think that's the direction we ought to be looking to try and sell the story of what blood really does.

DR. GILCHER: I'm going to reiterate the same things, but in a slightly different way. If I were making the recommendations, the first would be the importance of blood on the shelf, and I say that in terms of pre-donation--or, I'm sorry, pre-disaster donations, that is, the regular blood supply and the importance of getting that message out to the public all the time.

The second point is the unified message that needs to come from some high level of government after there is a very rapid assessment of the disaster that has occurred so that we don't end up with an overwhelming response and also two different messages. I think that's very important.

And that leads to my third point, which is that the massive donations that do occur lead to two things: the increased risks of error and, in addition, the decreased ability to make all the components from the blood because we're handling so much on the front end.

But those would be my recommendations.

DR. BRECHER: Do we have any comments from the public--oh, I'm sorry.

MR. DALAL: I'm sorry. I thought we were going in line here, but probably not, but I'll make a comment since I have the mike now.

I do want to reiterate this issue of trust. There is a unique bond, I believe, between the American blood donor and the blood banking communities. And I think this is a fundamental trust that needs to be maintained, and I suspect from the discussions that I've been privy to that this trust is being frayed as a result of, for example, mixed messages, mixed signals from different parts of the community.

That being the case, I think the situation is always going to be a dynamic situation where at times we're going to be going to the community and asking to down--or reduce the number of donations at a time of national emergency; at other times as related to CJD, we're looking to increase the number. And so there will be different messages, and the question then becomes: How do you manage this dynamic environment? And what type of an organization do you want to put in place?

And, Steve, to your comment earlier about the private nature of the way we're organized, I would encourage us thinking about putting in place an interim structure that has the right representation of organizations such as the ARC, the ABC, AABB, FDA, HHS, and even manufacturers, to deal with a situation if, for example, the news media's talking about further emergencies. What would happen if tomorrow there was another emergency? What would we on an interim basis do? How would we respond to that crisis while we're trying to solve the longer-term strategic issues related to communication.

DR. DAVEY: Yes, I certainly agree with what's been said.

First, I personally think trust is pretty good. I think most people are fairly confident that the people involved in this are clearly moving in the right direction and are caring and dedicated to doing the job. But I think there are some things we can do, and maybe just--I hope I'm not repeating too much, but I would also encourage--I don't know what we want to call it, but some kind of a definitely clearly designated and rapid response group that would include not just the government, because I know the government does have their conference calls on blood and that's very well and good, but one that would include--again, I think the obvious players are Red Cross, ABC, AABB, CDC, FDA, DOD, and those key players that can quickly and very specifically be brought together immediately when any kind of a disaster occurs. I think it's a very good idea.

Also, in addition, with regard to this specific committee, I would like to see that recommendations that we make with regard to anything, funding, whatever, that we are assured that they are brought to the highest levels and there are decisions and actions on those recommendations. I'm not sure that's always conveyed back to us very clearly.

And I guess, thirdly, I would think that perhaps this committee or the government could take a more active role in encouraging public officials to step forward--this has been mentioned earlier--to donate blood, to make PSAs, to see if we can get the President, the Vice President, somebody very prominent, to come on board in a very public way and saying this is important.

DR. HOOTS: I walked away from the discussions with a number of pieces of important information, I think, and I'll finish up with how I think we might should go with it, but I may, depending upon what the chairman's prerogative is, now or maybe when we discuss it later.

But the first was actually information that was imparted to this group yesterday morning, which I had received earlier from Harvey at the American Society of Hematology, where he reviewed the response to September 11th. And he showed to me, at least, for the first time what the age demography was of the donors and how many first-time donors and how many young first-time donors there were. And then we have subsequently heard, and he had already--he showed at that time that, you know, obviously what happened in terms of the huge outpouring and what that did in terms of oversupply.

So that communication which we heard yesterday as, "Pray, donate blood," or "donate money and donate blood," was heard. It was heard loud and clear, and it was heard by people who otherwise probably wouldn't have listened to other messages. I was particularly proud because I have two adult children who heard that message, independent of me, went out and donated in two disparate parts of the country for the first time in their life. So it was heard.

And I was therefore somewhat dismayed to know later that, first of all, that these are not returning donors. Secondly, that the blood was in excess at that moment in time. And, Bill, as a member of this committee and also as a citizen of the United States, we have got to correct that. We have to take this precious resource that was spontaneous and find a way to exploit it beneficially as a national resource for whenever we need it, but not use it when we don't need it.

So the second piece of information that came out was from what Ron was talking about in terms of his experience in Oklahoma and the really strong message about the value of redundancy and decentralization of capacity in response to disasters. And I think that's something that we all know intuitively, but has been proven now pragmatically on a number of occasions. And I think any new recommendations have to keep that in mind.

I think another one was from Mike when he was talking about the military, and I was thinking about the young reserve of individuals who donated for the first time. In the military they have a built-in system. People come in with the expectation that they might be asked or probably will be asked to donate. They may not be asked to donate four times a year every year, but they are asked if they are needed.

We have that prerogative, at least not so much to coerce but to cajole in the general population as well, but in order I think for us to effectively use that capacity, we have to develop a system so we don't exploit it like happened with excessive donations at one time and then inadvertent loss of donations later.

And so that's where the communication didn't work from the government. The government got the message out loud and clear to these people: You need to donate blood. Probably the wrong message. Part of the reason was probably because the message was wrong. "Donate money" was right. "Pray" was right. "Donate blood" was probably not right. "Offer blood" probably was the right advice to have been given. And if we had a system where the system could say, "If you're willing to offer your blood, we're going to make sure it's used at the time and the place where it's most efficiently utilized," then I think we will have done a very great service not only as a committee but as citizens.

And so finally, then, I will come back this afternoon with some ideas that I came up with after trying to put some things together.

DR. HEALEY: Thanks. I think in a lot of respects the government communicated too well in the wake of September 11th. I think that's clear from the outpouring of donors and the inundation or deluge of donations that came. That was a very effective message that was sent and was heard and people responded to, as Dr. Hoots has mentioned.

I think, though, it was clear from the testimony of Red Cross and others that it wasn't just Red Cross; that the government played a strong hand in having that message communicated to the country. But I think it really raises questions about the role of government, working with NGOs, non-governmental entities, and others in developing communication messages that are going to be sent by a private or quasi-private sector.

And those are questions raised that I don't particularly have answers to. I think that that relationship has to be carefully assessed anytime that the government is helping develop or setting messages to be delivered by the private sector.

And I'm sympathetic to the role of government here because I really think they have sort of a Hobson's choice. I think on the one hand they are charged with the responsibility of helping assure the safety and availability of products, and we see that through CJD deferral questions and other things which may raise questions and concerns on the part of donors. And on the other hand they're charged with the responsibility of helping maintain adequate supplies and reassuring the public about the availability and adequacy of blood and plasma therapeutics.

So I think they are really charged with, you know, walking a tightrope, and I think by and large do a really good job at it. There are obviously examples where it's more or less problematic. September 11th was one of them. Some of the confusion about the anthrax vaccine for postal workers might be another. But overall I think those questions have to be examined, those issues have to be examined kind of case-by-case, and by and large I think it works fairly well.

DR. LINDEN: My thoughts were very nicely articulated by Ron, although I really agree with everything that has been said, so I won't repeat everything. Basically, I think there is a need for a strong, effective, consistent message up front, so that we can maintain a good supply on the shelves, and then when there is a disaster of some sort, a strong, effective, uniform message at that point I think would be really helpful.

MS. LIPTON: I think most of what I wanted to say has been said. I absolutely agree with Celso. This issue of transparency, transparency builds trust, and we need to be transparent in terms of why we collect blood and what we use it for. And it really starts from the bottom, and not worrying so much about, well, what method do we think is going to sell, as much as getting out there what we really need blood for.

The next thing I'm going to say, I'm confident will not be universally embraced by every member of this committee, but I remain distressed that in all of the communications, that we still cannot seem to come to grips with the fact that donors are a public resource. They do not belong to any organization. They belong to all of us, and they belong to the public. And I really believe that there is a role for public education to which all organizations subscribe. That's different from donor recruitment, which is a one-to-one.

But when we talk about public messaging, we should all be at the table, we should all have one message, and we should be out there. It shouldn't be somebody's campaign, it should be all of our campaign. And, you know, I think it's just a shame that we have been unable in the past year now to come to grips with that. I think everyone expects us to do this, and I think we ought to get on with the business of doing it.

CHAIRMAN BRECKER: Okay. Well, I think there clearly were some miscommunications that occurred, mixed messages that went out to the public that we can learn from. In this most recent crisis, our blood collections doubled and our outdates quintupled, so that we collected over 500,000 additional units and in excess of 100,000 units were discarded, and I don't think we want to do that again.

In the context of blood donation, the Constitution does not guarantee the right to bear arms for donation. Sorry. I wish to reiterate that those units that were most important in the crisis were already on the shelf.

And I think it was Mike that said that there is no currently identified scenario in which the medical need for blood in a domestic disaster would exceed the ability of industry to respond. We can do it. We may need a better job of coordinating those efforts and knowing where the inventory is, to move it to the proper places, but the inventory is there for virtually any disaster that we can imagine.

We also learned from this that the use of emergency personnel, which the agency did allow in this instance, at least on a temporary basis, although well-intentioned, led to high rates of unusable units. So that's something I think we need to reconsider.

And another side effect of this overcollection is that there was decreased fractionation of whole blood, which led to decreased production of platelets. The laboratories were overwhelmed, again leading to decreased availability of platelets. And so we have to consider prioritizing platelets if this sort of disaster happens again, and we need to communicate that clearly.

Finally, I have to agree with Karen and everybody else that we really need a coordinated response. We need to know who to call to run this, and we need redundancy in the system, because wherever we put our coordination center, our crisis center, that may be the site of the next terrorist attack. I think New York learned that when the crisis center for New York City was located in the basement of the World Trade Center. So whatever we do, we have to have complete redundancy.

And then I think we need to look at the model from the U.K. for the monitoring of the blood supply. That does, I think, a wonderful job and picks up, I think they had close to 70 percent of their inventory was being monitored. If they can do it, we can do that as well.

DR. LOPES: I agree with everything that has been said about the short-run, immediate need situations. I'd like to raise an issue here about longer-run communication with the public.

I think that there is a serious problem, that we underestimate the intelligence of the public and their desire for deeper information. We blame sound bites on people's lack of knowledge about these things, but there are relatively few alternatives. People who have access to the internet know now that if you really want to find some information about something, say anthrax, you go to the internet because you are not going to find it on any of the media sources.

I think that we have a role to play here in providing better information to people about some of the very issues that have been brought before this committee. Obviously, the language needs to be changed to talk to a general public, but I think of things like the taxonomy yesterday about the relationship between blood type and what is done with particular blood types.

Things like substitutes for blood; educating the public about thinking about doing with less blood. I have a friend who is an OB/GYN. She has to fight with her patients who don't want to take iron pills. They want, if they have lost blood, they feel tired, they think they should have had a transfusion. But her own experience has led her to say no, this is not something that we should have as our only model here.

The profiles of the past events, we had an article in the package that was mailed to us about the actual needs for blood in major catastrophes are much, much smaller, I think, than the public could possibly understand. To have some public profiling of the kinds of events such as Dr. Gilcher has experienced firsthand.

I think that this can be done through the media, but not through public service announcements and certainly not through marketing. We see people turning sometimes to cable sources like Discovery, and they are really fascinated by programs that have some content for them.

I think that this group might be thinking ahead to how we actually create educational programs that people would find interesting, particularly in times of need. They maybe wouldn't turn to these in preference to other kinds of entertaining shows at other times, but when there are times of need, I think that we can speak more deeply to the public and satisfy their need for good information.

MS. PAHUJA: I think that in a manner of speaking we've gone about using the word "disaster" in a little bit of a wrong way. The disaster issue here is really that the situation in terms of blood supply was the same before September 11th as it is after September 11th.

That's really what needs to be communicated, this idea that disaster in the blood community is an issue of consistency of supply, not a natural disaster or a terrorist event. While those are very important and very fear-provoking, the real issue is, as many people have said before, this idea of having blood on the shelf that will help the people in need immediately. And without a consistency, it doesn't really matter how much blood you collect afterwards, which was really the education I kind o