Thursday, May 2, 1996

Omni Shoreham - Diplomat Room

2500 Calvert Street, N.W.

Washington, D.C.

The Presidential Advisory Committee convened at 9:05 a.m.



JOYCE C. LASHOF, M.D., Committee Chair











DR. ROBYN NISHIMI, Executive Director






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PAGE Call to Order

Dr. Joyce C. Lashof, Committee Chair 4

Health Effects of Low-Level Chemical Warfare

Agent Exposure

Colonel David Moore, Medical Research

Institute of Chemical Defense,

U.S. Army 4

Dr. Richard Jackson, National Center

for Environmental Health, Centers

for Disease Control and Prevention 35

Health Effects of Multiple Vaccines

Dr. Philip K. Russell, School of Hygiene

and Public Health, The Johns Hopkins

University 65

Dr. Anna Johnson-Winegar, Medical,

Chemical, and Biological Defense

Program, U.S. Army 83

Colonel John Brundage, Center for Health

Promotion and Preventive Medicine,

U.S. Army 96

Antidotes to CBW Agents: DOD

Dr. Anna Johnson-Winegar, Medical,

Chemical, and Biological Defense

Program, U.S. Army 139

Lt. Col. David Danley, Medical Systems

Program, Joint Program Office for

Biological Defense 155

Antidotes to CBW Agents: FDA

Dr. Stuart Nightingale, Associate

Commissioner for Health Affairs 184

Committee and Staff Discussion: Next Steps 226

Adjournment 237

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CHAIR LASHOF: Good morning. I think we are ready to resume our deliberations.

We welcome Dr. Jackson and Colonel Moore, who are going to talk to us this morning on the health effects. Colonel Moore, are you starting off?


COLONEL MOORE: Madam Chair, Committee members, good morning. I am Colonel David Moore and I am the Deputy Commander of the United States Army Medical Research Institute for Chemical Defense. That is located in the Edgewood area of Aberdeen Proving Ground, north of Baltimore, Maryland.

I am a veterinarian by professional training. I hold a Ph.D. in physiology from Emory University School of Medicine and I am a Diplomat of the American Board of Toxicology. I have been involved for the past 12 years in the Medical Chemical Defense Research Program, and three of those years I served as the Program Director. I welcome this opportunity to be able to provide

input on the requested information this morning. The next viewgraph, please.

Madam Chair, it is the conclusion of the Army Surgeon General that, in the absence of acute toxic effects, there are no observable long-term effects on humans of exposures to low levels of organophosphorus nerve agents.

I have been asked by the Committee to lay out the basis for this conclusion and I hope to be able to do that by showing that the preponderance of scientific evidence supports that conclusion.

Organophosphorus nerve agents, such as

Sarin--GB, Soman--GD, Tabun--GA, GF, and VX are highly toxic and extremely dangerous chemicals and were designed specifically to kill and incapacitate enemy forces, to disrupt operations, or to deny terrain.

What is a toxic effect? The effects of nerve agents are primarily the result and are related to the inhibition of the enzyme acetylcholinesterase and the resultant overabundance of acetylcholine at cholinergic synapses. Acute toxic effects, such as miosis, or pinpoint pupils and blurred vision, can be elicited at very low concentrations of nerve agents and lethal effects can be elicited at somewhat higher concentrations.

It is our premise, therefore, that an exposure to nerve agent which fails to reach even the threshold of clinical signs during or immediately following an exposure will have no observable long-term health consequences.

After the synthesis and testing of organophosphonate nerve agents by Schrader in Germany in the mid-1930s, this class of compounds has become one of the most widely-studied classes of organic chemicals in terms of their physical properties, their toxicity, and their physiological effects. Studies of their mechanism of action supported, to a large extent, research which has described the mammalian cholinergic nervous system.

Data available on human exposures to nerve

agents comes from two primary sources, accidental exposures and human experimentation. The next viewgraph, please.

Over the past 50 years, hundreds of

industrial and laboratory workers have been accidentally exposed to asymptomatic and symptomatic levels of organophosphonate nerve agents.

The strongest evidence in humans of a possible long-term health effect is described in a widely-cited study by Duffy, et al., in 1979. In this paper, it discusses EEG changes in non-human primates following both sublethal and multiple threshold exposures to agent Sarin, GB, and describes EEG changes found in a group of 77 workers with histories of one to three symptomatic exposures to nerve agent GB.

EEGs in this group were compared to those of a control group from the general population. There were subtle but statistically significant increases in EEG beta-band activity over the controls that were observed one to six years after exposure in the GB-exposed group. GB-exposed individuals were also reported to have more and

longer periods of REM sleep than the general population. However, the control group in this particular study had the same effect.

These 77 workers were reporting no adverse health effects and no behavioral changes. No behavioral effects in humans or animals could be attributed to these EEG changes. The authors of the paper, however, did speculate extensively as to the significance of their findings. The next viewgraph, please.

Between 1958 and 1975, the United States Army conducted research involving over 6,000 soldier volunteers to learn how specific chemicals may affect humans. Of this group, over 1,100 subjects were exposed to low to moderate levels of nerve agents under controlled conditions. The level of exposure was generally less than or equal to 1.5 times the IC-50. The IC-50 dose is defined as that dose which causes minimal incapacitation, that is, miosis, in 50 percent of the exposed population.

In 1982, the U.S. Army requested that the Committee on Toxicology of the National Research Council conduct a study of the possible chronic adverse health effects on servicemen who had been exposed to chemical agents under experimental conditions. The charge of this group was to determine, based on the available data, the clinical and case files of the volunteers and the current scientific literature, if it was possible to demonstrate the likelihood of a long-term health effect or delayed sequelae.

The first report found no evidence to support a finding of adverse long-term or delayed effects following exposures to nerve agents. However, this report was unable to rule out the possibility that some anticholinesterase agents produce long-term adverse health effects in some individuals. The report deferred to the outcome of a follow-on morbidity study to shed further light on this particular issue.

In the follow-on study, the long-term health effects of particular interest were excess cancer risk and adverse mental, neurologic, hepatic, and reproductive effects.

The study was a questionnaire survey of the current health status of over 4,000 subjects voluntarily exposed to chemical agents from 1958 to 1975. The report concluded for the nerve agents that the subjects exposed to anticholinesterases, as a group, were no different from the non-chemical test comparison group or from the remainder of the test subjects. The panel could neither confirm nor contradict, however, the findings of Duffy, et al., in 1979.

It is important to point out that there was a borderline significant increase in the numbers of malignant neoplasia in men admitted to the Veterans Administration hospitals, not Army hospitals, who had been exposed to anticholinesterase agents. There was no particular clustering of neoplasias and the numbers involved were very small. One was expected and four were observed. There was no evidence of association with a particular chemical exposure noted. The next viewgraph, please.

The majority of closely controlled toxicological studies have been conducted in animals, and of these, the majority have been conducted at the National Center for Toxicological Research or the University of California and were conducted under EPA health effects guidelines and current good laboratory practice standards. The next viewgraph, please.

In vitro and in vivo assays, as outlined on this and the next viewgraph, are highly sensitive indicators of a chemical's ability to damage genetic material, either as a mutagen with direct effects on the DNA molecule, or as a clastogen, with direct effects on chromosomal material. By being highly sensitive, it is highly unlikely that there would be false negative results and much more likely that there would be false positive results.

In these cases, agent GA, or Tabun, was shown to be a weak mutagen by demonstrating mutation rates in these tests of less than or equal to two times the controls, which is the minimum criteria for a positive response. Agent GA has not shown to be a teratogen or to cause birth defects in studies in two animal species.

The next viewgraph outlines similar in vitro and in vivo assays that were conducted on agents VX. In addition to these sensitive toxicological screens, there are extensive subchronic toxicity studies in various animal models.

These studies were also conducted under EPA and good laboratory practice standards at the National Center for Toxicological Research. These include 90-day subchronic studies of agents GB, GD, and GA in four separate studies; teratology studies of agent GA in two animal species, and developmental toxicity studies of agent GD, Soman, in two animal species. All these were essentially negative over a wide range of parameters. The next viewgraph, please.

The ability of certain organophosphate pesticides to produce a delayed neuropathy, commonly referred to as organophosphate induced delayed neuropathy, has been recognized for some time and can be demonstrated most effectively in a leghorn hen animal model. Numerous studies dating back to the early 1970s have attempted to demonstrate this effect with organophosphorus nerve agents.

This viewgraph outlines the results of 11 studies with G-agents and three studies with VX attempting to demonstrate this delayed neurotoxicity. With the G-agents, no neuropathy nor inhibition of neurotoxic esterase, thought to be the mechanism for the delayed neuropathy, could be demonstrated at levels less than 11 times the median lethal dose of the nerve agent. These animals had to be pretreated and treated with atropine and 2-PAM chloride just to maintain survival on the study.

No neuropathy nor inhibition of the neurotoxic esterase was found with agents VX. This is in sharp contrast to some organophosphate pesticides. The next viewgraph, please.

Organophosphate pesticides and

organophosphonate nerve agents have much in common but differ significantly in their acute toxicity and some physical properties. Some of their targets and some of their effects also differ.

Specifically, nerve agents of the

organophosphonate group do not produce an organophosphate pesticide-like delayed neurotoxicity at concentrations that are achievable with vapor exposure. Therefore, extrapolation from pesticide effects as it relates to delayed neurotoxicity is inappropriate. It is our position that the data generated with organophosphorus nerve agents are sufficient to support our conclusion

relating to this potential long-term health effect. The next viewgraph, please.

The Department of Health and Human

Services was mandated by public law to review the Department of Defense's plans for transporting and disposing of lethal chemical agents and to make recommendations for protecting human health. The preliminary report and recommendations were published in Morbidity and Mortality Weekly on February 12, 1988.

After addressing public and agency comments, the final recommendations for protecting the health and safety against potential adverse effects of long-term exposure to low levels of chemical warfare agents was published in the Federal Register on March 15, 1988.

Human exposure limits set by the Department of Defense are detailed in reports of McNamara, et al., which have been provided to the Committee. The final DoD and Health and Human Services recommendations did not differ significantly.

In the final recommendations of Health and Human Services, it stated, "Questions related to the nerve agents proved relatively easy to resolve. The information bases are fairly complete, and there appears to be little risk either of adverse health effects from long-term exposure to low doses or of delayed health effects from acute exposure." The next viewgraph, please.

While there is extensive data on threshold, sublethal, and lethal concentrations of nerve agents in animals, few data exist on subthreshold or asymptomatic exposures. What is known regarding asymptomatic exposures in humans relies primarily on subjective measures. It is also unlikely that additional data on asymptomatic accidental exposures in humans will be obtained. As of today, the relevance of the reported EEG changes after symptomatic exposures to nerve agents remains unknown.

With that said, Madam Chairman, the vast preponderance of both human and animal data supports the conclusion that there are no observable long-term adverse health effects following exposure to asymptomatic levels of nerve agents.

Subject to your questions, that completes my briefing.

CHAIR LASHOF: Thank you very much. I think we will take questions for Colonel Moore at this point and then proceed with Dr. Jackson afterwards.

Colonel Moore, I would gather that from your presentation--well, let me not put it that way. Do you believe that there are any further studies that need to be done, or are you satisfied that we have done all the research that we need and that this is pretty much an answered question and it would not be necessary or prudent to spend additional funds researching this?

COLONEL MOORE: Being a scientist, I do not think you can ever say that there is always enough evidence to support a conclusion. A conclusion has been drawn from the available data and I think it is a matter of priorities as to whether additional studies on this particular topic will be done. Really, as a worker bee in the research community, I would take guidance and I would support guidance, but we have made a position. We have taken a stand in terms of the available data.

As I mentioned, there are no studies specifically on extremely low doses of chemical warfare agents in animals over a long term. That is a possibility, that that type of information can be gathered.

But if you can extrapolate from higher doses to lower doses, which is commonly done, I think there is a large body of evidence that supports this conclusion.

CHAIR LASHOF: In April of this year, April 25, we had a memo from DoD stating that they will devote more attention to researching the possible effects of low-level subacute exposures to chemical warfare agents. Do you know what studies they had in mind in that memo, or are you involved in those?

COLONEL MOORE: We have no guidance at our laboratory to conduct those studies and I know of no ongoing studies addressing specifically that question, no, ma'am.

CHAIR LASHOF: Thank you. Are there other questions?

DR. NISHIMI: Colonel Moore, the airborne standards for OP nerve agents for the general population and for occupational exposure limits are quite low, apparently 1,000 times lower than what can be detected on the battlefield, is that correct?

COLONEL MOORE: That's my understanding. DR. NISHIMI: Then why shouldn't we

provide soldiers with the same level of protection as we do for the general population and other occupations?

COLONEL MOORE: I think we do provide the best protection to soldiers under operational conditions, but if you were to say, how can we use engineering controls on a battlefield that we would use in, say, a chemical demilitarization plant for workers that are employed there in complete bubble suits and so forth, I think that that would be impractical.

DR. NISHIMI: But we consider the Army standards, let's say for the general population, anything above that, the Army would consider to be hazardous to the general population, is that not correct?

COLONEL MOORE: That is correct.

DR. NISHIMI: But the Army wouldn't consider that to be hazardous--

COLONEL MOORE: That is hazardous. These are extremely hazardous chemicals and we provide--I think we are attempting and we always have attempted to provide the best protection on the battlefield for soldiers against chemical warfare agents.

DR. NISHIMI: But is it not correct that you cannot detect that level on the battlefield?

COLONEL MOORE: To be perfectly honest

with you, I am not a detection specialist and I cannot answer that question. That's my understanding, though. Those recommendations for workers in demilitarization facilities or the general population outside--those levels, I know, in the final recommendations of the CDC, they state that those cannot be detected and that engineering controls in the facilities have to provide that type of levels of exposure.

DR. NISHIMI: So we shouldn't draw any conclusion that the very low levels that you set have long-term effects because those levels are so low?

COLONEL MOORE: I do have a slide that shows--it takes the toxicity from a "no effect" level down to those very, very low levels, and I can show you how those were based. The idea was that we would get very, very low levels that would never approach the "no observable effect" levels and it is based on those "no observable effect" levels that we can extrapolate the long-term effects.

CHAIR LASHOF: Why don't you put the slide up, because I think this is a key question, since what we are concerned about is levels that aren't detectable by our equipment and whether that falls into the low level that you feel has no effect or not.

MS. TAYLOR: You have to look at the comparable airborne levels to see.

COLONEL MOORE: These are figures that were taken from McNamara's report on developing control limits for general population and for workers. There are some approximations here, but the LCT-50, or that concentration of agent per minute per cubic meter that causes lethality in 50 percent of the population for a man at rest is approximately 100 mg per minute per cubic meter.

If you were to take those other doses, one

is called the "no death" dose, one is called the "no neuromuscular effect" dose, and the next one is the ECT-50 and it was referred to also as the ICT50, or the incapacitating dose for 50 percent. It is about 2 to 4 mg per minute per cubic meter.

That particular one is actually measured

in man. The others, the higher levels, are estimates. The "no observable effect" level is a half a milligram per minute per cubic meter. So it is above that particular level that you would expect to see symptoms of exposure. When basing and designing control limits, you try to determine what levels a person can be exposed to over time that would never approach that "no observable effect" level.

So the maximum safe concentration for one

hour was estimated to be the level that you see there, 0.001 mg per cubic meter. You can see that is quite a bit lower than the "no observable effect" level. But then when that is taken over an eight-hour period, a time-weighted average for eight hours, it adds on an additional half-a-log increase in safety.

Then when those figures are applied to the general population, an additional log safety factor is added which takes it to even those lower levels, which I believe some of those lower limits clearly are not detectable by our current standards.

So I just want to show you where we are in terms of low levels for human safety in terms of decimal points to what is known to be the "no observable effect" level and what is known to be a symptomatic exposure, which would be at 2 to 4 mg per minute per cubic meter. As you can see, they are quite, quite low.

CHAIR LASHOF: The level at which we say the "no observable effect" level, is that the level at which you would say that there is no long-term effect at that level, or at what level did you go to when you come to the conclusion that--

COLONEL MOORE: We do have significant data of evidence in humans that at doses above the "no observable effect" level, at the levels up at the ECT-50 and above, where there is no observable long-term health consequences from that exposure.

So our conclusion is that if you can get

no observable long-term health consequences from an acute exposure at that level, then these extremely low doses, it follows that you don't have any longterm health consequences from those. That's the basis for our conclusion.

MS. LARSON: What is the cutoff point for what our machines can detect?

COLONEL MOORE: I'm sorry, I don't know that. You may have to address that to a detection specialist.

MS. TAYLOR: It's much higher than 0.0003. Most of the equipment that's currently available can't detect levels that low, airborne concentrations at all. It could be--I've seen 0.001 or 0.01 largely, but never as low as that.

COLONEL MOORE: I can't say that it is clearly below the--I mean, it is much lower than the "no observable effect" level. That is clear. But it is not down into the six decimal points.

CHAIR LASHOF: Have there been any studies

of the combination of the nerve agents with other drugs, such as pyridostigmine bromide, which has been hypothesized to have a synergistic effect?

COLONEL MOORE: Clearly, not in humans in

combination with nerve agents. Those types of studies clearly cannot be conducted today. But there is a substantial data base of animal studies that were pretreated with pyridostigmine in an effort to demonstrate the efficacy of that particular pretreatment against the broad spectrum of chemical warfare agents, all the G-agents and VX and GF. So there is a large body of evidence that supports the efficacy of pyridostigmine as a pretreatment in animal models.

CHAIR LASHOF: But were those animal studies that were looking at the issue of

pretreatment also looked at whether those animals were followed and whether there were any long-term effects of the combination?


CHAIR LASHOF: They just looked at the-COLONEL MOORE: Just looking at the

effectiveness of pyridostigmine.

CHAIR LASHOF: For the acute prevention of toxicity?


CHAIR LASHOF: I see. Thank you.

Are there other questions? Yes, Elaine? MS. LARSON: Colonel Moore, I don't

imagine that you can answer this, but I do want to raise it because I think it is important. We have heard testimony from a number of folks who had symptoms that might have been related to exposure, so they were above the "no observable effect" level. It would be helpful for us to know what battery of tests they have undergone so that we are, in fact, screening for the appropriate toxicities and so forth.

For example, did they have EEGs and all that kind of thing? Can we find that out, Robyn?


MS. LARSON: Thank you.

CHAIR LASHOF: Mark, do you have


DR. BROWN: Yes. Colonel Moore, I guess the basis of your testimony is that if you look at the literature on the effects on man of these chemical agents, that in the absence of acute effects, you would not effect any long-term effects? I think that summarizes it in a nutshell.

COLONEL MOORE: That's right.

DR. BROWN: But what about the issue--we know that some of these agents have cumulative effects. That is to say, they can cause damage to enzymes cumulatively over a prolonged period if you have exposure.

I guess the scenario I am thinking about that is most directly relevant to the Gulf War situation is the possibility of exposure over hours or perhaps even days at low levels. Does the information that we're talking about here help us address the issue of the possibility of cumulative effects that would manifest themselves not necessarily as acute effect but over a period of time might, nevertheless, build up to an actual long-term health situation?

COLONEL MOORE: That did not apply to the premise that I set up today. The premise that we had was that there was an exposure or there was a cumulative exposure that did not result in acute toxic signs. In that particular case, I think we can look at the data and we can assume that there is no observable long-term health consequences.

If you're asking if there is sufficient

data to look at levels, let's just say, of the maximum safe concentration for more than an hour, let's just say for two days at that level, in animals, that data does not exist, and I pointed that out on my conclusion slide. So that is a potential data gap in the total picture.

DR. BROWN: That would represent a potential data gap, then, in our understanding of

what could have happened with exposures?

COLONEL MOORE: That is correct.


MR. CAPLAN: Can you tell us, in the way the animal studies are conducted, is there enough genetic heterogeneity so that we would be able to pick up predispositions or differences in the biological constitution of the animals to low-level exposure, or are we talking about pretty pure-bred standardized stock here?

COLONEL MOORE: Yes. When I described the toxicological screens, those are standard toxicological screens that we would use in screening any toxic chemicals and they are standard laboratory-bred pure genetic strains that have to be utilized in that way to be considered under good laboratory practices. So there aren't any deviations from that standard screening, those types of tests that have been conducted.

MR. CAPLAN: So a heterogeneous population, let's say, in humans, we have some evidence from those volunteers, but-

COLONEL MOORE: That's correct.

MS. TAYLOR: I just have one follow-up

question to what Mark asked earlier regarding cumulative effects. In looking back at the two human studies that you mentioned in 1982 and 1985, the volunteer subjects, how long were they exposed to the nerve agents at low doses?

COLONEL MOORE: Those were acute exposures at that level. Those were acute exposures.

MS. TAYLOR: Acute exposures?

COLONEL MOORE: Acute exposures, one-time exposures and then information was gathered in terms of effects, heart rate, blood pressure, things of that nature, a battery of tests. Those were not long-term, chronic exposures.

MS. TAYLOR: So they weren't--for

instance, in the work setting, we would sample an area, a work area, for several days. So this is not that at all?

COLONEL MOORE: No, ma'am, but it is from that type of data that these figures, the ECT-50 and the "no observable effect" level, were determined, so we could then add safety factors that brought us down to--

MS. TAYLOR: Point-zero-zero--

COLONEL MOORE: --to six decimal points. MS. TAYLOR: Thank you.

MR. CAPLAN: Just one last question. Do you know, are there any long-term follow-up studies being done from the Japanese subway incident?

COLONEL MOORE: To my understanding--this

is just hearsay, but I understand that the Japanese are taking an active role in gathering that information. The Americans are not involved in that. We do have a Japanese physician coming to visit our laboratory next month who was the chief physician at the main central hospital in Tokyo where those casualties were taken to discuss treatment regimes and modalities with us, but I don't have any personal information on any epidemiological study or follow-up study. But my understanding is that they are pursuing that.

MAJOR CROSS: Colonel Moore, yesterday, we

heard testimony that dead animals were actually

shipped back and they did a post-mortem check on them and they didn't find any evidence of death by chemical weapons. Can you shed any more light on that?

COLONEL MOORE: I don't know the results of the study. It was conducted at the Armed Forces Institute of Pathology and I don't know any of the details of that study. I'm sorry. But it's never been reported to our institute that they were associated with organophosphorus nerve agents.

MAJOR CROSS: Let me just ask a simple

question, because I'm sitting here and I'm assuming that you've made your evaluations based on the documentation here, but the question in my mind is, if these nerve agents won't necessarily cause harmful effects in humans under these test conditions, why would third world countries like Iraq weaponize these agents if they wouldn't cause some effect?

COLONEL MOORE: No, clearly, these agents at very low concentrations--and I can assure you that the LCT-50, the lethal concentration 50, the acute toxicity of these agents is very low, 100 mg per minute per cubic meter. These are extremely toxic and extremely lethal and battlefield concentrations and vapors can be put out on a battlefield that kill humans very effectively. That's why they weaponize these. They did not design them to cause long-term, low-dose chronic effects. These are lethal weapons.


DR. BROWN: Colonel Moore, some of the veterans that tell us about the health problems that they have had after coming back from the war talk about problems that occur many years, maybe more than one year, after their return from the Gulf.

The information that you talked about in terms of chronic long-term effects from a low-level exposure or high-level exposure, the Institute of Medicine study where soldier volunteers were used and some of the other studies that the Army itself did, how long did those studies look at the exposed populations? How long were they monitored for possible health effects? Are any of them appropriate for that time frame? Did any of them look at a time frame of years?

COLONEL MOORE: Just to review that again, the exposed population was between 1958 and 1975. The first review by the Committee on Toxicology was in 1982 and they went back and looked at the case files from the individuals and looked at the morbidity and the health consequences from the exposure from that perspective.

From the case files, they could determine that there had been no long-term effects, but they also wanted to look at what the current health status of those individuals were in 198, and so they did a follow-on morbidity study in which they looked at adverse neurological, hepatic, reproductive, cancer risks, and so forth. That's the extent of that study. Those individuals were not monitored monthly between 1958 and 1982.

DR. BROWN: But presumably, they would have picked up effects that took, say, several years to manifest themselves?

COLONEL MOORE: That's correct. That's the thought.

MAJOR KNOX: Colonel Moore, do we have any evidence that these chemicals were not stockpiled to use as low-level toxicity--

COLONEL MOORE: To be perfectly honest with you, I don't have any personal knowledge or information about stockpiling of the weapons. I'm sorry. I couldn't answer that one.

CHAIR LASHOF: I think we can move along. COLONEL MOORE: Thank you.

CHAIR LASHOF: Thank you very much,

Colonel Moore. That was very helpful.

Dr. Jackson?

DR. JACKSON: Good morning, Dr. Chair, and members and staff of the Committee. I am Dr. Richard Jackson of the National Center for Environmental Health of the Centers for Disease Control and Prevention based in Atlanta.

I am here today at the Committee's request to talk about what are the lessons we can learn from organophosphorus pesticides. This is an issue, actually, quite close to my background. I started with the California Department of Health Services about 15 years ago as a physician epidemiologist--I'm a pediatrician--working in the area of pesticides. California leads the nation in the use of pesticides, particularly the highlytoxic organophosphates and corbamates, and leads the nation also in numbers of pesticide illnesses recorded each year.

I also had the experience during that time of dealing extensively with examining the impacts of exposure to low levels of organophosphates to very large populations, first in the early 1980s with the proposed and subsequent application of Malathion aerial bait over several million people in the San Francisco Bay area multiple times, and then in the early 1990s in Los Angeles.

As a result of the Los Angeles application program, we put together in the California Department of Health Services this review of the impact of the use of Malathion, low levels, to very large, heterogeneous public populations. We had excellent help from all across the Department of Health Services, including a chemist named Mark Brown.

Also in my time in California, I was head of infectious disease, as well, and came to CDC about a year and a half ago. CDC has had extensive experience in dealing with, of course, infectious and chemical weapons. Our shop in CDC at HHS provides the oversight to the United States Department of Defense related to the chemical weapon demilitarization program.

I think there might be some information that we can glean from looking at what happens with exposure to organophosphates in large populations and what we might be able to learn from this experience in the Gulf War situation. I think there are three critical pieces of information we need to deal with this.

One is, what was the exposure? Has

exposure occurred, and at what level was that exposure?

Secondly, what is the nature of the agent?

What is its inherent toxicity, and does it have delayed effects as well as acute effects?

Then thirdly, what is the nature of the population being exposed? Are there sensitive individuals?

The first issue, related to what is the level of exposure, the critical issue here is that the dose, of course, makes the poison. Each of us lives in a sea of toxic agents, many of which are cholinesterase-inhibiting compounds. The measurement of these agents is usually done by measuring air or water or food or surfaces in our environment, and yet what we really want to know is, what is the dose that human beings are actually being exposed to? What is the internalized dose?

That is an area where CDC has worked very

hard in providing that real human data, which I think is powerful in the decision making process. These measurements, of course, are of much more use than recollections of what exposures were a long time in the past.

One experience we had in considerable depth was that of Dioxin related to Agent Orange exposure. The half-life of Dioxin, which is an obligate contaminant of 245-T, is about eight to ten years in humans. In the past, the way to measure Dioxin was to actually take a fat sample, a biopsy of about ten to 50 grams of fat, and analyze Dioxin.

This was clearly impractical and in the early 1980s, CDC devised a method where we could actually measure Dioxin in the less than one percent of fat that exists in our blood. So we could take blood samples and actually measure Dioxin in the blood levels of individuals.

In the studies that were done related to Agent Orange were compared the levels of Dioxin in ground troop veterans in that study, controls low, medium, and high self-described exposures, and also amongst ranch hand veterans. The ranch hands were the individuals who were actually loading and being involved in the application of the Agent Orange.

What was found in that investigation was,

in fact, the highest levels of Dioxin exposure were in the non-flying enlisted men. The second-highest levels were in the flying enlisted men, then in the officers. The next lower level was in the nonflying officers, and then in the controls. The ground troop levels were quite low.

The take-away lesson from this is that the recollections that we could get from individuals about, where were you, what were you exposed to, what color was it, how many weeks were you there, tended to be fairly unreliable compared to actually getting the gold standard, which is how much is in your body.

With Dioxin, it was relatively easy, not that it's easy to measure parts per quintillion in large populations, but it was relatively easy in the sense that the Dioxin remained in the body for a long enough time that we could actually measure it. It's much more difficult when you have evanescent exposures, exposures that will occur and the body eliminates them relatively quickly.

That was the case when we looked at volatile organic compounds in fire fighters who

were exposed to oil well fire smoke in Kuwait. CDC staff and people from other agencies conducted cross-sectional surveys of workers in Kuwait City in May of 1991 and of fire fighters in the oil fields in October of 1991. Blood samples were tested for 31 volatile organic chemicals--these are relatively rapid turn-over chemicals in the body-and compared to a referent group of persons living in the United States collected as part of NHANES, National Health and Nutrition Examination Survey Number 2, done by the National Center for Health Statistics, part of CDC.

As you would expect, the median concentration of volatile organic chemicals among the fire fighters was quite elevated. However, among the non-fire fighting personnel in Kuwait, VOC, volatile organic concentrations, were equal to or lower than the levels found among the reference U.S. population. This suggests that the smoke from the oil well fires did not pose a significant additional health threat to the individuals in the area beyond the exposure to the fire fighters themselves.

We also worked with the Department of Defense in a study of 30 members of an Army unit located in Germany which was dispatched to the Gulf. Blood from each of these military personnel was tested for volatile organic chemicals at three points in time: Before they went to the Gulf, while they were there, and upon their return.

Only one compound of the 31 chemicals that

were analyzed was found to be elevated during deployment and that compound was tetrachloroethylene, perchloroethylene. It's a compound that's used in degreasing agents and used to clean equipment.

This reflects not only the fact that we have worked with DoD on these investigations but also the importance of having pre-, during, and post-real time measurements and getting of specimens when it actually occurs.

So I've talked about the importance of the exposure, and it's relevant, I think, not to get too enmeshed into the discussion of toxicity until we recognize how much were people actually exposed to. So I have talked about exposure. I would like to talk about inherent toxicity in the nature of the agent for a minute.

In the area of pesticides, they are

extraordinarily diverse in terms of their toxicity. They are, in fact, used because they are toxic, and of the seven million chemicals that are registered for use, about 1,500 or 1,600 are the active ingredients that are sold as pesticides in the United States. About 15,000 overall are pesticides worldwide.

The organophosphates include some of the most acutely toxic and potentially lethal of the pesticides that are in use. They have come into use because they are used and degrade relatively rapidly in the environment as opposed to chemicals that we have gotten rid of over time, the ones that are fat soluble and tend to remain in the environment, such as DDT.

They have a high potential for acute toxicity in humans compared to other types of

pesticides and pose a significant risk for persons involved in the manufacture, mixing, formulation, and application of these chemicals. They have less potential for chronic health effects or environmental contamination, and unlike Dioxin, which stays in the body for a long time, these compounds remain for only a few days and can be only directly measured shortly after exposure or indirectly measured by taking cholinesterase measurements of the blood.

As I said, these compounds vary in potency. For example, the LD-50, the lethal dose 50, for Malathion is about a gram per kilo, about 1,000 mg per kilogram of body weight of the person being exposed, and this compares to the LD-50 for commonly-used more toxic pesticides, such as Parathion and Aldicarb. Aldicarb is a carbamate, which have toxicity ranges in the 1 to 5 mg per kilogram range.

In contrast, the LD-50 for Sarin is about a half-a-milligram per kilo. So even though we think that there is a wide range, there are actually chemicals that are being used in the agricultural workplace that are not that far from the toxicity range of war gases.

As was mentioned, they exert their action by inhibiting cholinesterase and the frequency of the signs and symptoms vary with the route of exposure. Clearly, if you are exposed by the respiratory route, usually, you expect to see respiratory symptoms first. If you have ocular exposure, it is often the ocular symptoms that appear first. And as we often have seen with ingestions, for example in homicide and suicide type events, GI symptoms, gastrointestinal symptoms, are often the first to appear, although any kind of mixture can occur with these chemicals and it is very hard to say something didn't occur because you only have two of ten expected symptoms.

There are reports of delayed onset

peripheral neuropathies after acute and chronic organophosphate exposure. These are actually killing off of the longer nerves. They are killed back by the neurotoxic esterase and other toxic elements in the organophosphate, and over time, in many individuals, these nerves will regrow. This is a well-documented, known effect of certain subgroups of the organophosphates.

There have been a number of epidemiologic studies of sequelae in acutely-poisoned individuals. If you are acutely poisoned with these compounds, there have been studies that have shown, for example, Savage's study, that there are neuro-behavioral changes in these individuals over a long period of time. But the people I'm talking about are acutely ill, documented individuals with known organophosphate poisoning.

In California, one of my colleagues, Richard Ames, did a study looking at subclinically poisoned individuals, or subclinically exposed individuals. These are individuals who were pulled out of the workplace because they had blood measurements that showed depression of their cholinesterase. They had not shown symptoms yet, but they were at the range where you would remove them from the workplace.

He and Kyle Steenland and others went back and did neuro-behavioral testing in these individuals to see what happened and we could not document, the group could not document residual effects in this population. So if you're clinically ill with an organophosphate, there does appear to be identifiable neuro-behavioral effects over time. If you were not clinically ill, you had biochemical evidence of exposure but not clinical illness, we have not yet documented long-term effects in that population.

The third piece of information needed to decide on the public health impact of the exposure is the nature of the exposed individual. This is a very difficult issue. It's one that one of your Committee members, Dr. Philip Landrigan, and I served on his committee with the National Academy of Sciences on pesticides and the diets of infants and children, we have grappled with this long and hard. It is a very difficult issue about the heterogeneity of the population.

Clearly, we are not all 70-kilogram, healthy, 22-year-old males. The surface-to-volume ratio of humans varies widely. An infant has four to five times the skin surface for every pound of body weight that an adult does.

We differ markedly in our behaviors. Infants will have extensive hand-to-mouth exposure or rolling on the ground, a lot of dermal exposure, whereas in work settings, some workers can adhere closely to worker protections. Other workers may be much more heavily exposed, smoking, eating without washing up, not wearing respiratory equipment, or whatever. So the behavioral changes are quite relevant to this exposure.

The third part of the heterogeneity is that we are biochemically and biologically heterogeneous. Probably one in a couple hundred of us have a variation in butyryl cholinesterase levels in the blood. This is an agent in the blood that buffers cholinergic agents in our environment. This may actually make us make that subpopulation somewhat--in fact, it is known to make them more susceptible to certain agents, such as Tacrin, a drug used for Alzheimer's disease and medications used in anesthesia.

A think a number of important lessons come out of the worker and community exposure to cholinesterase-inhibiting pesticides. The first is that many poisonings have occurred with symptoms as severe as with any nerve agent. While the acute symptoms are well known and documented, it is still debated, what are the long-term sequelae of these poisonings.

There is little information documenting effects from chronic low-dose exposures, such as the kind that all of us receive from pesticide residues in our diet. Dr. Landrigan and I did a section in this report modeling actual dietary exposures in the population. There are about two dozen organophosphates that are used in food. Each of us have consumed these yesterday in our food.

Various Federal agencies monitor these

chemicals in food, and what we did was do a Monte Carlo analysis, generating ten million theoretical meals for children, and could find that about one

percent of children per day are in a range where they have exceeded a reference dose for just five of the organophosphates that are in our diet. So as you consider these discussions, realize that there is a low level of background exposure to these chemicals pervasive in our environment.

I think that there is no way to prove a negative. There is no way to absolutely say that there were no significant exposures to nerve agents in the Gulf. It is with the absence of identified overt clinical symptoms and with the absence of striking measurements of exceedances--and this is an area I don't know a lot about--but where you have monitors in the field that are measuring exceedances, I think I'm in the range where I'm almost talking about food.

We can speculate these exposures are occurring, we can speculate there might be some effects, but I don't have enough evidence to really say what these could be.

These conclude my prepared remarks and I appreciate the time and attention of the Committee.

CHAIR LASHOF: Thank you very much. It is

open for questions.

DR. NISHIMI: Dr. Jackson, would it be a fair--just to make sure that I got the bottom line here--that we would not see any long-term health effects in an individual exposed to any OP agent unless we had also seen acute symptoms?

DR. JACKSON: Ms. Nishimi, the number of studies that have been done on subclinically exposed individuals and doing long-term looks at that population, that's a very limited group. I'm just reporting to you, when it has been looked at, it has not yet been identified, but those studies are usually 75 to 100 people. These are not large populations. They're not enormously heterogeneous populations.

I could not state categorically there would be no effects. I have to tell you there's a public policy decision de facto to allow low-dose exposures to organophosphates by our whole food regulation system and that de facto decision would imply that we believe that there would not be effects.

CHAIR LASHOF: In terms of the research, the question I asked Colonel Moore, really, in your view, are there unanswered research questions and would there be validity to do additional research at this point on the low-level long-term exposure in different individuals, and what do we know about the biological differences that might impact on sensitivity or responsiveness to these agents?

DR. JACKSON: This is a very hard area in the sense that every time you follow one of these trails, you always end up saying, gee, we need to know more about what is the actual mix of these compounds. What they tell us is a technical-grade ingredient, for example, with a pesticide, turns out to be a whole bouillabaisse of chemicals that is in there. What happens when someone is taking another cholinesterase-inhibitor at the same time or is on medication or has a butyryl cholinesterase deficiency?

I think these are important questions. I think, just as we have been very concerned about

cancer in the past, I think the effects, the neurotoxic effects of agents in our environment ought to be an area of considered research by our society. I think these are important areas.

Specifically, the whole issue of delayed neurotoxicity is one that deserves more research from a general standpoint. I don't know the nerve gas/war gas literature well enough to say that that's true in that area.

MS. LARSON: Just to follow up on that point, you did say that there have been reports of delayed onset peripheral neuropathies after chronic OP exposure. That chronic exposure also resulted in clinical symptoms, or how was chronic OP exposure defined?

DR. JACKSON: I'm sorry. The chronic OP exposures were in workplace settings where individuals were exposed to compounds that were known to contain neurotoxic esterase-type compounds and were risk factor compounds for delayed neuropathy.

Most of the really bad--let me start over. Many of the compounds that were known to have delayed neuropathy risks, such as Leptophos and others, have been removed from the agricultural setting. So I don't think it's as clear an issue any longer in the agricultural setting. From the Colonel's testimony, and I don't mean to speak for him, I heard him very clearly state that this does not appear to be the case in the war agent setting.

MS. LARSON: But my question is, one of

the premises is that if there are no symptoms, there is no long-term risk, and my question was, in these where there have been in the past delayed onset peripheral neuropathies after chronic OP exposure, were there symptoms?

DR. JACKSON: At chronic higher-level exposure, people have developed the neuropathy with certain of these compounds that contain neurotoxic esterases.

MS. LARSON: Without--

DR. JACKSON: Yes, so they had symptoms. MS. LARSON: They did have symptoms?

DR. JACKSON: They had the symptoms of the delayed neuropathy. I cannot right now tell you if they had the acute symptoms in the workplace setting earlier.

MS. LARSON: That is the whole point that is being made here, and it would be important to see if there is any precedent for that.

DR. JACKSON: I would be happy to research that for you.

MS. LARSON: Thanks.


ADMIRAL CASSELLS: In the same vein, Colonel Moore said it was not appropriate to compare the nerve agent organophosphates with the pesticide organophosphates, but clarify for me, aren't the signs and symptoms of acute poisoning essentially the same in both instances and that it's a matter of how much you're exposed to?

DR. JACKSON: I think we're actually

saying the same thing. I think for acute toxicity, it's reasonable to compare the compounds in terms of cholinesterase inhibition. I think for the delayed neuropathy, with the absence of known

documented delayed neuropathic effects of the war agents and the presence of known delayed neuropathic effects with the pesticides, I think your point, and I don't mean to speak for you, is that we should treat them separately for the delayed effects.

COLONEL MOORE: That was my only

assertion, that there are organophosphate pesticides that have shown delayed neurotoxicity, but in extensive studies to demonstrate that with the nerve gases, the organophosphonates, we have been unable to demonstrate that in a very sensitive animal model and extensive numbers of studies.


DR. BROWN: A question for Dr. Jackson. It sounds to me, if somebody was interested in setting low-level effects of exposure to organophosphorus agents, I mean, you mentioned that some of the studies that exist out there only used populations of 100 people and so forth.

If you wanted to do better studies, more extensive studies, the population that we might be most interested in is our civilian population who we know are exposed to organophosphorus pesticides, that that would be the best population to take a look at these, if one were to do further studies on the chronic low-level effects of organophosphorus agents.

DR. JACKSON: I have tried to do many studies related to environmental exposures in the civilian population, the non-occupationally-exposed population. They are extremely difficult to do because of the evanescent nature of exposure and getting people to work with you.

I think you really have to turn to workplace settings where you have known industrial hygiene measurements, you can actually follow these people, you have a Social Security number, a birthday, you can follow them over time. I think there are lessons that can be learned from the occupational setting. Trying to learn from these much lower exposures in environmental settings, let's say after Malathion applications in Southern California, it's very, very hard.


ADMIRAL CUSTIS: I am left with the adage that some of my friends take an affirmative stand, some of them take a negative stand, and I never disagree with my friends.

MS. TAYLOR: I guess what it sounds like, if you don't have a large exposure from an--and I think Mark mentioned it earlier--a large-dose exposure from chemicals like GB or some of the others, then you don't have anything. We don't know. There's no long-term effect. You have to be killed, in other words, for getting the intended effect.

DR. JACKSON: The studies have been done on people who were either sick or very close to being sick and not done on lower-level-exposed populations and those studies are extremely difficult to do.

MS. LARSON: Is it also accurate to say that given the short half-life of these agents, it is impossible to study now this question in the Persian Gulf veterans?

MS. TAYLOR: It would be hard.

MS. LARSON: It's no longer there. DR. JACKSON: You could tell from my

points that I think there are some real lessons about the importance of persons being sent into

certain settings, that you need to have specimens on those individuals before they go. You need to have an ability to at least sample those individuals in a certain kind of setting and then the ability to monitor them afterwards.

I think it was very useful in being able to say what happened to those fire fighters. It was useful being able to say what happened to that small group of soldiers in terms of the volatile organics.

It hadn't dawned on us, nor was I on board at that time, to do this kind of study. I think one could have probably looked at biological levels at that time. It's not that hard to devise methods.

MS. LARSON: But it is important to think about the future and that surveillance needs on site and what needs to be planned for in the future.

CHAIR LASHOF: If I can just follow up on that, because one of the responsibilities of the Committee is to make recommendations for future policy so that we don't find ourselves in this position again. Has CDC looked at what it would take and devised any theoretical models of how they would recommend surveillance for a deployed population going into different areas? Have you thought about this at all?

DR. JACKSON: We have thought about this. It is a problem area for CDC, I'll tell you bluntly. CDC was not engaged in the Agent Orange activity. When eventually Congress felt that the veterans needed to be followed up and instructed HHS to do it, we were charged to do that. There was a large infusion of resources, staff, laboratory efforts into looking at it.

When that came to an end, it disappeared. There is not a single staff person that is funded and directed to work on veterans activities until the Gulf War episode appeared, and then there was another redirection. We are now doing a study in Iowa, comparing 10,000 Iowa veterans who served in the Gulf versus 10,000 veterans who did not. Actually, that will be a very good sample of a profile population who went over. But I think the episodic nature of CDC's involvement has been difficult for us.

CHAIR LASHOF: Compared to your ongoing responsibilities on infectious disease surveillance, is that correct, that it doesn't compare?

DR. JACKSON: Infectious disease, we always have to maintain someone that knows something about leptospirosis and rabies and a whole string of other diseases. They can be transferred over and provide some assistance on these questions. The questions that come up related to battlefield settings tend to be often unexpected and much more specialized, however.

CHAIR LASHOF: Thank you. Other


MS. LARSON: Just to follow up a little more, obviously, it's impossible and it would be not cost effective to monitor everybody for everything, but with 700,000 people deployed in a conflict, one could figure out a sampling technique that would make it possible without breaking the bank to be able to prevent these things in the future.

CHAIR LASHOF: Or at least to be on top of them.

MS. LARSON: Yes, to be on top of them, sure.

MS. TAYLOR: I was just thinking, maybe if everybody wore a personal monitor while they were serving--

MS. LARSON: Yes. We have ATM machines that can do great things, and we have all kinds of marketing things, Internet, things that are beyond what any of us in this room can handle. Certainly, we can take some of those techniques and apply them to the military.

Then I would also just like to remind us again that there were a number of people who did, in fact, have symptoms of--or potentially symptoms of acute exposure and we need to look at how those were followed up as well as this issue of low dose. I know it's not on our topic, but I just don't want us to forget it.

DR. JACKSON: May I correct something? We had 10,000 Iowa veterans. They were a subsample, and there were 1,500 exposed and 1,5000 comparison, just to correct the numbers.

CHAIR LASHOF: Thank you very much. We appreciate your appearing today. It was very helpful.

We are right on time. We are scheduled for a break at this time.


CHAIR LASHOF: I would like to resume now, if everyone will take their seats, please.

Dr. Russell, Dr. Johnson-Winegar, and Colonel Brundage, welcome. We appreciate your coming today and we are going to hear discussion of the health effects of multiple vaccines and I believe you are going to start, Dr. Russell.


DR. RUSSELL: Thank you very much, Dr.

Lashof. It is a pleasure to be here in response to the Committee's request to discuss immunization in military populations and more specifically the potential adverse effects of immunization.

I must state up front that I am a member of an IOM committee on the health consequences of service during the Gulf War and I also serve on an IOM committee to study the interactions of drugs and biologics in U.S. military forces. My appearance here is in my personal capacity and I am not representing the views or the findings of either of the IOM committees.

CHAIR LASHOF: But you take the same position at every one, I assume?

DR. RUSSELL: Pardon me? Immunization is a very important issue for the military because of its proven effectiveness in preventing illnesses and death. The success of smallpox and poliomyelitis global eradication efforts are

inspiring events in the field of vaccinology. Vaccination is also a very important issue in global public health because it is fundamentally the most cost effective public health intervention.

Military leaders are especially interested

in vaccine because it preserves the combat effectiveness of forces. U.S. armed forces have benefitted by the use of vaccines since George Washington used variolation to protect the Continental Army against smallpox epidemics that were ravaging the military forces at that time.

As new vaccines were developed and brought into use, some by the general medical community and some by the Army, the Army has added more and more vaccines to its routine use. The Army has developed a whole series of vaccines specifically because of the nature and the magnitude of the problems facing the Army. It started with typhoid vaccine at the turn of the century and the latest developed vaccine was Hepatitis A, licensed last year.

We have two populations in our society that are immunized intensively with a number of vaccines, including combination vaccines. These are infants and military recruits, and they are immunized for fundamentally the same reasons. Both groups are at very high risk of infectious diseases and they have little protective immunity. Infants receive up to 17 vaccine administrations in the first 15 months of life. Several of them are in combination, such as DTP and measles, mumps, rubella.

In addition to this, there is every

expectation that in the next few years, we are going to add several new vaccines to the pediatric schedule, which include multivalent streptococcal pneumonia vaccines, conjugated, trivalent rotavirus vaccines, respiratory syncytial vaccines. I would expect we will see influenza vaccination of infants in the future.

Our military recruits are given booster doses of several of the pediatric vaccines, including measles, mumps, rubella, polio, diphtheria, and tetanus. In addition to that, immediately on entering the military service, they are vaccinated against a series of respiratory infections because of the tremendous susceptibility of military recruits to respiratory epidemics. These vaccines include influenza, meningococcal meningitis, and adenovirus disease. All three of these are combination vaccines.

After recruit training, troops are additionally exposed to the diseases endemic in the developing world if they are deployed offshore and additional vaccines for deployment include typhoid, Hepatitis B, yellow fever, Japanese encephalitis, and rabies vaccine. Added to that, we have to consider the use of additional vaccines to counter the threat of biologic warfare, depending on the military intelligence situation.

Safety is a primary consideration in the development and use of vaccines and it is addressed both in the pre-licensure studies, both animal and human volunteer studies, and in post-licensure surveillance. There is no perfectly safe vaccine and some risk-benefit ratio has to be considered

for every vaccine. It is a biologic product and individual responses are not 100 percent predictable.

All vaccines have some level of

reactogenicity. They cause local reactions. Vaccines induce an immune response and that immune response creates redness, swelling, fever, and most of the symptoms and signs of infection are related to the immune response to fight that infection. Many vaccines cause fever in some subjects and rarely they cause a severe anaphylactic reaction. In addition to that, there are specific safety issues that are related to each individual vaccine, for example, the issue of full inactivation of inactivated viral vaccines.

Assuring safety of individual vaccines is an extensive but relatively straightforward process. It consists of pre-licensure studies in cell cultures in animals, testing in volunteer subjects, and then after licensure, safety evaluation continues through post-licensure surveillance of vaccinated populations.

Some of the problems can be detected in animal studies, but fundamentally, the kinds of problems that we're concerned about, especially low-frequency adverse events, can only be detected in surveillance of large immunized populations.

A much more complex question than the

individual safety issues for vaccines is the potential for an adverse effect of multiple vaccinations, whether in combination or

simultaneous administration of multiple vaccines or repeated vaccinations, such as the annual influenza vaccine, or the repeated immunizations that are given to laboratory workers.

The underlying question is, can intensive immunization produce immunopathology or other serious adverse events? Of special concern would be displasias or malignancies of the immune system.

In addressing this question, we have to

recognize the fact that even the most intensivelyimmunized individuals, the antigens received through vaccination are a tiny part of the huge number of antigens that the human immune system has to deal with. Stimulation of the immune system occurs continually after birth, from normal bacterial flora of the oral, the respiratory, and the gastrointestinal mucosa, and from diseasecausing organisms.

Antibodies are produced against a wide variety of organisms that colonize in mucosal surfaces. These populations are continually changing. A course of antibiotics will totally change the bacterial flora and result in a different set of immune stimulations.

Invasive organisms cause even more vigorous response. Every cold, every earache, every bout of bronchitis, episode of diarrhea, every flu-like illness, every minor infection exposes the immune system to very large numbers of antigens and they stimulate both cellular and humoral response. Viruses during infection may produce from three to 30 protein antigens that stimulate immune responses. Bacterial infections probably expose immune systems to thousands of antigens.

So the human immune system has evolved with the capability to deal with these antigens, to sort them out, to regulate its response in order that we can live in a population of bacterial and hostile microorganisms, and I think it's a fundamental truth that the immune stimulation from vaccination is a small part of the total immune stimulation from naturally-occurring microorganisms.

Nonetheless, there is concern that extensive use of biologic products which are, indeed, biologic products and are not chemically characterized, such as drugs are, could have an adverse impact on the immunized population.

This has been addressed by several investigators and two committees that I know of. The National Research Council Committee on Effects of Multiple Immunizations has looked at this issue at the request of the Army back in 1980. They reviewed the extent of the medical literature at the time and they also reviewed the studies of the intensively immunized workers at Fort Detrick.

Their conclusion was no conclusion,

fundamentally. They saw no evidence in the animal and experimental studies that there were adverse events. The studies of the individuals showed some minor abnormalities but none that could be linked to the vaccination, nor did they appear serious. That committee did, as most committees do, recommended further study of the issue.

It is a fundamentally important issue for childhood vaccination, as well, because of the increasing number of childhood vaccines. In 1994, the Vaccine Safety Committee of the Institute of Medicine published a study on adverse effects associated with childhood vaccines and they did address the question of multiple vaccination, especially the possibility of immunosuppression.

Their conclusions supported the concept

that I stated previously, that the amount of immune stimulation from vaccine was very tiny compared to the natural immunization process that goes on with children. They saw that there was no evidence for overload of the immune system.

The NIH and the Food and Drug Administration sponsored a meeting in September of 1994 to address the issue of development of new combination vaccines, combinations such as DTPHemophilus influenza, DTP-Hepatitis B-Hemophilus, and so forth. At that meeting, Dr. Parkman, who was the previous director of the Office of Biologics of the FDA, addressed the issue and he stated that, "The literature is virtually devoid of studies suggesting clinically significant enhancement of adverse reactions by such use."

I think that is basically where the scientific community stands, for the most part, today, that although there are adverse reactions to individual vaccines that are well known, the fundamental problem of over-immunization per se is not known to cause adverse events.

On the other hand, there is every reason to continue to look at and to study the probability of low-frequency events occurring from vaccine and from multiple vaccine. I think these issues are

not easily addressable in the experimental animals.

Experimental animals have a much different immune system than man and the human immune system is down-regulated much more than the experimental mouse or guinea pig.

Therefore, we are fundamentally required to look at the studies in man to provide the best possible assurance. I think in the civilian world, the CDC is doing a very good job in developing post-licensure surveillance studies to look for low-frequency adverse events in the pediatric population, as well as in the adult population immunized with such vaccines as influenza and pneumococcal pneumonia.

The military has some unique capability to do this. I think we will hear some testimony later on what some of the possibilities might be. It will be essential that the medical record keeping of both the armed services and the Veterans Administration, as well as some attempt to capture data from the civilian medical system, be carried out. We need better medical records if we are going to be able to search for the low-frequency adverse events and relate them to interventions during the course of preventive medicine interventions.

It is quite possible to do some much larger volunteer studies in military populations, and I think we will eventually come to the conclusion that we need to do much more extensive studies than we have done in the past on populations in garrison and in training, where the studies are much easier than they are during deployments.

I think I will stop there, Madam Chairman, and I will answer any questions.

CHAIR LASHOF: Thank you very much.

Let me follow up on your very last point about what kind of further studies ought to be undertaken by the military when they are giving so many vaccines over such a very rapid period of time. I'm not sure, is there any other population that gets quite that number of vaccines in such a very brief period of time as the military?

DR. RUSSELL: Only a very small population, such as the laboratory workers in the Fort Detrick laboratories and some other laboratories. Those populations should be looked at and followed, both for their own sake and for what scientific information we get from them. But they are too small, I think, to provide the level of assurance that we're looking for.

I think we really need to improve our ability to find sentinel events within the military medical system and to relate those to the immunization experience and other experiences in military populations.

CHAIR LASHOF: We can't design the research right here, but it seems to me that there are a couple of issues around that. One, indeed, is how good their immune response is to all the different vaccines that are given, whether you get as good a response to each of them as you would if they were given separately, and then this other question of adverse reactions.

I would assume the adverse reactions, if we're going to have them, would be acute, within a

few days at the most. So it wouldn't be a long study you would need to do but to keep tabs more quickly, or not? Am I wrong on that?

DR. RUSSELL: I think the vast majority of adverse reactions are acute, within the first 48 hours. There are a few that may extend weeks after vaccination. On the other hand, we are looking at theoretical issues relating to displasias of the immune system and long-term immunosuppression and things like that.

Immunosuppression, for example, does occur very profoundly with the wild-type measles under natural conditions. You get a smaller level of immunosuppression from the vaccine, the attenuated vaccine. That may last a month. Whether it has any clinically significant effect is very, very doubtful. I have never heard of any instance that it would in the military situation.

CHAIR LASHOF: Thank you. Other questions the Committee has for Dr. Russell? We are going to take questions after each speaker this morning.

MAJOR KNOX: Dr. Russell, can you tell us,

the immunization or the immunosuppression that occurs, does it affect both the T-cells and the Bcells?

DR. RUSSELL: Pardon me? I can't hear you.

MAJOR KNOX: The immunosuppression that occurs, does it affect both the T-cells and the Bcells? Is it pretty broad?

DR. RUSSELL: The immunosuppression that occurs after measles immunization? Yes, it is across the board. It is a very broad-based--it is a total suppression of the immune system, and it-

MAJOR KNOX: But it only lasts about one


DR. RUSSELL: Probably a lot less than that in most instances, yes.


ADMIRAL CASSELLS: Dr. Russell, you stated that there was little evidence to support the contention that multiple immunizations resulted in increased adverse reactions. Are there any comorbid conditions that might change that?

DR. RUSSELL: I think that is the kind of thing we are looking for if we set up long-term post-use surveillance systems. I don't know of any co-morbid situations that might change that. I suspect that perhaps occult diseases of the immune system, lymphoma or something like that, might, but--

ADMIRAL CASSELLS: Do you have any speculation as to whether it would be manifested as increase in adverse reactions to specific vaccines or a new condition entirely, or do we not know?

DR. RUSSELL: I don't think we know. I

don't think we have any information on that.

DR. PORTER: Dr. Russell, you stated that small animal studies have little value in looking at long-term effects of vaccines. Does that suggest, then, that use of small animal models in and of themselves will never be sufficient in presenting safety and efficacy data that could result in vaccine licensure when it's not possible to conduct the studies in human beings because of ethical considerations?

DR. RUSSELL: Small animal studies are very valuable in looking at safety issues unrelated to the immune response. Acute toxicity issues, issues of possible contamination, other adventissuous [ph.] agents. There is tremendous value to small animal studies.

On the other hand, small animals have a very active and vigorous immune system and they do not predict the immune response of man. Many of us who have been in the vaccine development field have been disappointed time after time after time when you see vigorous responses to vaccines in small animals, and man, very poor response. The human immune system is very much down-regulated with regard to responsiveness to many antigens.

It is also true that immune responsiveness is genetically determined, both across and within populations. So the genetics of small animals are so much different that they choose a different set of epitopes to respond to than man. So predicting human response from animal studies is very problematic.

So if you're looking at safety issues that relate to immune response and immunopathology, you really have to go to man to study them. The safety issues of other natures can be studied very well in animals.

CHAIR LASHOF: Any other questions? Robyn?

DR. NISHIMI: Dr. Russell, I know we asked you to comment primarily on the multiple vaccination issue, but would you say there is a similar lack of data or information about vaccine and then other chemicals in combination?

DR. RUSSELL: The interrelationship

between vaccines and--

DR. NISHIMI: The health effects of, right, vaccines and of pharmaceuticals taken.

DR. RUSSELL: There is a small amount of data on interactions. There are some vaccines that do change the metabolism of some compounds, influenza vaccine, for example, but it is a very small amount of information. Whether it is clinically relevant or not, I think, is a very open question. Again, if you are looking for events that are rare and may occur only under very special circumstances, you need a fairly extensive screening and detection system to find them.

DR. NISHIMI: And animal models, again, would be inappropriate because of the genetic-

DR. RUSSELL: You are doubly confounded

here because the mouse doesn't respond to the vaccine the same way man does. Neither does the mouse metabolize the drugs the same way, so you are doubly confounded with those kinds of issues.

CHAIR LASHOF: That's one experiment the

mice are safe.


CHAIR LASHOF: Are there other questions? If not, thank you very much, Dr. Russell.

Dr. Johnson-Winegar?

DR. JOHNSON-WINEGAR: Good morning. Madam Chairman and other members of the Committee, thank you for the opportunity to be here this morning to present some comments and answer your questions.

Just as a refresher, if I could have the

next viewgraph, please, I would like to review the questions that were specifically asked and to indicate that we will be answering those in turn.

First, what evidence exists of adverse

health effects resulting from multiple vaccinations used in the Gulf War?

Second, what is the DoD doing to investigate possible adverse health effects from those biologics and drugs used in combination?

And third, a comment on what is the DoD

doing to address possible adverse health effects in the future? The next viewgraph, please.

I would like to introduce myself to the Committee. I am Anna Johnson-Winegar. I have a Ph.D. in microbiology. I am one of those highlyimmunized people that works at the laboratory at Fort Detrick and my current position is that of Director of Medical, Chemical, and Biological Defense Programs for the U.S. Army Medical Research and Materiel Command at Fort Detrick.

To briefly review what Dr. Russell already mentioned in his comments, I draw a comparison to the fact that in addition to the military, the childhood population, especially in the United States, represents a large body of data, for, in fact, they do receive multiple vaccines. As indicated on this chart, some of those are diphtheria, mumps, tetanus, hemophilus, chicken pox, Hepatitis B, measles, rubella, and these represent a variety of different types of vaccines. Some are live attenuated viral vaccines. Some are inactivated bacterial vaccines, et cetera.

So in point of fact, over a number of years, both combination vaccines have been used and vaccines given multiple times have been used and there is no large body of data indicating that this is an undesirable or unwarranted practice. The next chart, please?

Again, referring specifically to military use of vaccines, shown here are a number of the different vaccines routinely administered to military recruits for a variety of reasons. Many of them are given as booster immunizations to compliment the initial series given during childhood and others of those are given because of disease threats for potential deployment and for operational considerations. Next, please.

We were asked to comment on what is the DoD doing to look at the health effects of multiple vaccines and drugs in combination. We have recently chartered the Institute of Medicine to do a specific study for us. As you will see here, the study is entitled "Interaction of Drugs, Biologics, and Chemicals in U.S. Military Forces: Current and Future Issues".

While we do not yet have a report from that Institute of Medicine, I would point out to you that they have recruited members from academia, government, pharmaceutical, and vaccine industries who bring with them to the committee a wide variety of backgrounds and should be able to address a number of different types of issues.

The committee will use commonly accepted standards to evaluate both the adverse effects and potential interactions for these drugs and biologics and we hope that the committee report

will give us some specific recommendations for screening studies or protocols that we can use in the future.

I would like to comment on one relatively small study that we have done, and before I do that, I wanted to just refresh your memory regarding the anthrax vaccine. That was administered to approximately 150,000 service members during the Gulf War. This anthrax vaccine is produced by the Michigan Department of Public Health. It is a fully licensed vaccine, licensed and approved by the FDA.

It is not to be confused with another anthrax vaccine that is made for veterinary purposes. The veterinary vaccine is a live attenuated spore vaccine of the stern strain, whereas the vaccine licensed for human use is a killed vaccine. It is made from a partially purified culture supernatant of an avirulent strain of Bacillus anthraces. It was licensed in the early 1970s, has been used in several thousand individuals, primarily at-risk laboratory workers, prior to its more widespread use during the Gulf War.

The specific study that I would like to summarize for you was conducted by USAMRIID. I apologize for the use of an acronym that you may not be familiar with. That stands for the U.S. Army Medical Research Institute of Infectious Diseases, located at Fort Detrick. The study was a retrospective study to look at the combination of anthrax vaccine and botulinum toxoid, which were the two vaccines administered during Operation Desert Shield/Desert Storm to protect service members from the two biological threats.

Basically, what we did was to go back and

find a study population who had received those vaccines. This study was done in 1992, and basically, we went back and looked at the combination of giving them a booster shot of anthrax vaccine and/or botulinum toxoid, either alone or in combination.

We found that in the individual administration of these two products, greater than 95 percent of the study group had no reaction at all, whereas if there were a combined administration, approximately 91 percent had no reaction. I would note that this is an additive effect, because we tallied both individual reactions and if an individual reacted to both anthrax vaccine and botulinum toxoid, it was counted twice.

Those reactions that we did observe could be characterized predominately as local reactions, and local reactions are defined as redness or anathema or slight swelling at the site of the injection, contrasted with systemic reactions in less than one percent of the population. A systemic reaction for the purpose of this study is defined as fever, malaise, headache, or other generic symptoms not localized to the injection site.

No long-term effects have been recorded. We have followed these individuals for four years now. We also note that there was no adverse interaction on the immune response to these two

vaccines, because we did take serum samples before and after administration to do a comparison and we showed that the individuals responded in accordance with previously predicated data.

MAJOR KNOX: Dr. Winegar, did you say what the sample size was on that study?

DR. JOHNSON-WINEGAR: Two-hundred-ninetyone.

An additional effort that we are undertaking is a tri-service relational database. This has recently been put forward as part of some studies to look at women in the military, and from these studies, we will be developing epidemiological data as well as other data, including immunization status. We hope that this will be able to allow us to compare to nationallyknown rates of injury and illness in those populations that can be segregated according to various different criteria.

Finally, I would like to comment on the current status of our work. I would point out to you that all of our medical, chemical, and biological defense products are developed and tested in accordance with the Food and Drug Administration regulations to support product licensure.

If we feel that the adverse interactions are warranted, we will do specific studies, as pointed out by Dr. Russell, and I will reiterate that. To date, we have seen none. There was one study previously conducted on hyper-immunized laboratory workers at Fort Detrick. We have recently approved another protocol to do a 20-year post-vaccination study, again, on highly-immunized personnel who work in our laboratories.

One piece of data that I found interesting that I wanted to bring to the Committee's attention was that the current industry estimate of the time and cost to license a drug or a vaccine is approximately 15 years and $291 million. This is from some 1994 data.

In conclusion, I would like to comment that the DoD does anticipate further research into this area. I have described one study for you specifically and we await recommendations and guidance for future work.

Subject to your questions, that concludes my prepared comments.

CHAIR LASHOF: Thank you very much. About the future research, your final

statement is you await further guidance.


CHAIR LASHOF: Could you amplify on what areas you expect to look at and what guidance you are looking for and where that guidance comes from

and how you are going to plan your future research? DR. JOHNSON-WINEGAR: Certainly. A key

piece of information for us will be the report from the Institute of Medicine, and we feel that they do have the appropriate criteria to help us look at that.

The other that I would mention to you is the specific study that we have just undertaken and we are recruiting subjects now for that from a highly-immunized population of at-risk laboratory workers. Other than that, we have no specific

plans at the moment.

CHAIR LASHOF: Could you put up the

viewgraph that showed the different vaccines that are used? I think it was about the third or fourth one there.

MS. TAYLOR: "Military vaccines" is what it is entitled.

CHAIR LASHOF: I really just wanted to ask you over what period of time those were given. Which ones are sort of combined and given one shot? Do you walk through and get them all in one fell swoop or over a few days? What is the routine?

DR. JOHNSON-WINEGAR: I am not an expert,

not being a preventive medicine physician, but it is my understanding that a number of those are administered during basic training over a period of several weeks.

CHAIR LASHOF: Dr. Russell, do you know that?

DR. RUSSELL: The immunization of military recruits includes influenza, adenovirus, meningococcal, mumps, measles, rubella, and polio, and that is usually given within the first few days. It is necessary to immunize the incoming recruits against adenovirus, influenza, and meningitis within the first few days, and so the in-processing is, at maximum, a week. Depending on the service, typhoid vaccine and yellow fever and other vaccines are delayed until later.

MS. TAYLOR: Hepatitis B is a series, though, is it? Hepatitis B is a series of different--

DR. RUSSELL: Pardon me?

MS. TAYLOR: Hepatitis B is a series. You can't take that just one time. You have to come in several times with that vaccine, right? Am I correct on that?

DR. JOHNSON-WINEGAR: Right, it's three doses.


DR. RUSSELL: Hepatitis B requires a series of immunizations.

DR. JOHNSON-WINEGAR: That's what I meant when I said over a period of several weeks to complete the immunizations, because some of those are, indeed, multiple dosage regimens.

CHAIR LASHOF: Right. If additional ones are added, I mean, those are the top and then at the bottom you have "tailored to disease threats of potential deployments". Those, obviously, such as the anthrax or botulinum, would be given much later at the time you were ready to deploy.

DR. JOHNSON-WINEGAR: That's correct. CHAIR LASHOF: It would be a rare person

that would get those at the same time they got the routine that everybody gets when they enter basic?

DR. JOHNSON-WINEGAR: That's correct. CHAIR LASHOF: You're not apt to get into

basic and be sent overseas at the same time, so we do have that kind of a break.


CHAIR LASHOF: Thanks. Are there other questions the Committee has?

MAJOR CROSS: Dr. Russell, what is the percentage of recruits that are discharged because of adverse reactions to these vaccines? Is it

small, or is it--

DR. RUSSELL: Pardon?

MAJOR CROSS: What is the percentage of recruits that are actually discharged because of adverse reactions to these vaccines?

DR. RUSSELL: I think that is a very tiny number, if any. What do you think, John? You can answer that better than I can.

COLONEL BRUNDAGE: I have never heard of such a case. That doesn't mean that it has not occurred, but I think that it is a very, very small number, if any.

CHAIR LASHOF: Rolando, do you have any questions?

MR. RIOS: Yes. Dr. Johnson-Winegar, in the present position that you have today, were you in that position during the time that we mobilized our troops to the Gulf War?

DR. JOHNSON-WINEGAR: No, sir. I was not the Director at that time. I was a member of the staff.

MR. RIOS: Was there any concern that you know of about the vaccinations that were being given to the troops?

DR. JOHNSON-WINEGAR: Certainly, I think that we had an abundance of data to indicate the safety and the immunogicity of the anthrax vaccine and the botulinum toxoid, which I believe you are referring to, those two vaccines?

MR. RIOS: Yes, but what I want to know is, was there any concern about administering it?

DR. JOHNSON-WINEGAR: I think concern is

an individual question, and I'm not clear whether you mean concern on the basis of the individual who was the recipient, or--

MR. RIOS: Was there any concern expressed by you or by any of the people around you as to whether or not the wisdom of giving this immunization at the time?

DR. JOHNSON-WINEGAR: The decision to administer those vaccines was a policy decision and was not made at our command.

MR. RIOS: I know, but was there any kind of concern that you were aware of, either by yourself or by any of your superiors, about the wisdom of giving it? I know that the policy decision was made by somebody else, but were you aware of any concern?

DR. JOHNSON-WINEGAR: Again, I would certainly say that the data that we had available certainly indicated that there was no concern regarding the safety of these products.

MR. RIOS: Is it true, what I have heard, that it was not FDA-approved at the time that it was administered?

DR. JOHNSON-WINEGAR: No, sir. I would repeat, as I pointed out on one of the other charts, that the FDA licensed the anthrax vaccine in the early 1970s and it is fully approved and licensed. The botulinum toxoid is an investigational new drug.

MS. TAYLOR: As a follow-up to Rolando's question, were there any known adverse reactions from combining those two vaccinations, the botulinum toxoid and the anthrax vaccine? Did we have any information to show that there would be

any increased health risk for persons taking both of those vaccines?

DR. JOHNSON-WINEGAR: The one study that I did summarize for you was a retrospective study of those vaccines given at the same time, and the data indicate that there was no increased adverse reactions.


MR. BALDESCHWIELER: It is my understanding that there are a number of different strains of anthrax. Is the Michigan killed vaccine effective against all of those strains?

DR. JOHNSON-WINEGAR: To date, we have tested that vaccine against a number of different strains and find that it is effective. There are slight variations in the levels of effectiveness, of course, but we feel that it is sufficiently effective to protect against all known strains.

MR. BALDESCHWIELER: All known strains? DR. JOHNSON-WINEGAR: All known strains

that have been made available to us and that we have been able to test, yes. Again, let me iterate, of course, that those tests were done in animal models. We do not test for efficacy in humans.

MS. LARSON: First, a point of clarification on your retrospective study, the one that's pictured up there. You said you did some immune response studies. How could you do that retrospectively? You would have to have pre- and post-, and as I understand it, the record keeping was sometimes a little bit poor, so how did you do this study?

DR. JOHNSON-WINEGAR: As I said, we did this study in a relatively small group, approximately 290 individuals. We drew a serum sample before they were given this booster immunization to see if they had remaining antibodies.

MS. LARSON: Oh, I see.

DR. JOHNSON-WINEGAR: Then we administered a booster vaccination and looked for a four-fold or higher increase in their titer.

MS. LARSON: So it wasn't before the initial immunization, it was at the booster?


MS. LARSON: A second question, one of the hypotheses that has been proposed, as I understand it, is that the anthrax vaccine might have been contaminated with microplasma fermentins incognitis somehow and have inadvertently been administered, that other organisms had been administered at the same time. Can you tell us how that might have happened, or could it have happened, and comment on that hypothesis?

DR. JOHNSON-WINEGAR: Certainly. In accordance with the FDA regulations and the license for the anthrax vaccine, each lot of vaccine is tested for sterility, among other criteria, and no lots of vaccine are released by the FDA or by the manufacturer should they fail any of those safety tests.

MS. LARSON: And these procedures were in effect in the lots that were given to the Gulf veterans?


MS. LARSON: Could you explain to us how microplasma is grown, how you would find it in a sterility test?

DR. JOHNSON-WINEGAR: It's a culturing type of test. It's a routine screening for contamination. I'm not sure--

MS. LARSON: So it would grow and it would be clear on the cultures? Obviously, I'm asking it so we all have the same understanding. Viruses don't grow on culture in the traditional bacterial on the plates. Microplasma do--


MS. LARSON: --and would they have been detected?

DR. JOHNSON-WINEGAR: Well, it requires a special type of growth media, yes.

MS. LARSON: Was that growth medium used in those tests?

DR. JOHNSON-WINEGAR: I believe so. I would have to check.

MS. LARSON: I think we need to check on that, because it is one of the important hypotheses and we would need to be able to rule out the possibility that microplasma--if we can--was a contaminant by knowing what procedures, because I believe that you would not pick up microplasma in the routine sterility tests, but I may be wrong, and we need to find out about that.

CHAIR LASHOF: Dr. Russell, do you have information on that?

DR. RUSSELL: I would just like to point out that this is a formalin inactivated vaccine and the probability of live microplasma persisting in that vaccine and infecting a vaccinated individual is extremely unlikely. I do agree, however, that the safety tests may not have picked up microplasma incognitis. It is a difficult organism to detect under some circumstances. I think it might be possible to look into the issue. There certainly are samples of those lots still available.

MS. LARSON: Then we could just lay that hypothesis to rest one way or the other and get it off the table. So if we do have those samples, that's wonderful.

DR. JOHNSON-WINEGAR: Yes. There are reference samples from all the lots that were produced that are still held by the manufacturer.

MS. LARSON: I'm just astounded, if that

is the case, why we haven't--I mean, this hypothesis has been in the literature and it's been out there for some years.

DR. JOHNSON-WINEGAR: I think, as Dr. Russell pointed out, for a vaccine that is a killed product and is inactivated with formalin, that is not a standard requirement.

MS. LARSON: No, I absolutely agree. That is the whole point. Why do we still have it on the table, then? If it is extremely unlikely in a killed vaccine, let's just resolve the issue once and for all.

MAJOR KNOX: I have a question. The anthrax vaccine, I think the DoD was proactive in giving those vaccines to us. However, for 700,000 troops to be deployed and only 150,000 to receive anthrax and 8,000 to receive botulinum, if we were to be deployed today and have that number of

troops, would there be enough vaccine to go around? DR. JOHNSON-WINEGAR: There is sufficient

quantity of anthrax vaccine available today, thanks to continued manufacturing since the onset of the conflict.

MAJOR KNOX: One of the problems that we came across during Desert Storm was there wasn't enough vaccine and the commanders were put in an area enclosed and they were told that they were to decide among themselves who was to receive that vaccine, and I think there needs to be some type of protocol to lay that out, such that the commander doesn't have to make that decision about his troops.

DR. JOHNSON-WINEGAR: That's correct, and you may or may not be aware that there is now a DoD immunization policy for biological defense vaccines.

MAJOR KNOX: So if there weren't enough vaccine to go around, would there be a protocol to address that issue?

DR. JOHNSON-WINEGAR: It's not a protocol, it's a prioritization of the high-threat units.


DR. NISHIMI: Was this study done on Gulf War veterans, the combined anthrax botulinum toxoid?


CHAIR LASHOF: Other questions? Tom? MAJOR CROSS: I have a question. If we

were to deploy troops right now to Southwest Asia again, would we give them the same vaccines here or are there other ones that you would, in retrospect, give, additional vaccines?

DR. JOHNSON-WINEGAR: The immunization policy that I referred to delegates the authority to make that recommendation to the Assistant Secretary of Defense for Health Affairs, in conjunction with review by the Joint Chiefs of Staff, to analyze the threat.

MAJOR KNOX: One of the vaccines that was not listed that I think that everyone received was the immunoglobulin, as well, was that not right, for Hepatitis A?

DR. JOHNSON-WINEGAR: If you want to call that a vaccine, yes. If you mean serum globulin, that's right.


DR. PORTER: I just wanted to follow up to ask when you expect further guidance to be forthcoming from the Institute of Medicine and from other sources that will help you think about future research studies.

DR. JOHNSON-WINEGAR: I believe that we expect a report within the next year. Of course, we will then have to review and analyze the recommendations that they make to us.

DR. PORTER: Would you expect that those follow-up research studies would be done both inhouse and through contracts and grants?

DR. JOHNSON-WINEGAR: That's generally the DoD approach, yes, is we make a determination as to the resources available to us, both from our inhouse laboratories and staff and also an assessment as to the interest and capabilities from potential contractors.

CHAIR LASHOF: Further questions? If not, let me just go back once more to the microplasma issue. The sterility tests wouldn't show it, but this is a formalin treated and formalin kills microplasma as much as it kills anthrax and anything else. So to find it would be more than unlikely. I mean, it would be a strange microplasma that survives formalin, would it not?

DR. RUSSELL: I don't think the vaccine

community is seriously looking at this issue, fundamentally because of that fact. The formalinization that is required to inactivate the toxins in the anthrax and in the botulinum is way above the concentrations that will inactivate or kill any microplasma or bacteria.

DR. JOHNSON-WINEGAR: And it couldn't be in the botulinum toxoid, either.

MS. LARSON: That's also formalin



MS. LARSON: That is important for all of us to hear, so that we have resolved it.

DR. RUSSELL: These two vaccines are toxoid vaccines. They don't contain the whole organism. They contain merely the toxoid that was excreted into the supernatant and then inactivated with formaldehyde. They are very, very similar to the diphtheria vaccines and the tetanus vaccine that is used in children. Those vaccines traditionally have very, very little problem with contamination simply because of the nature of the manufacturing process.

CHAIR LASHOF: So it would be fair to say that although you may have heard this theory being bantered about in the community, you wouldn't have bothered testing it because the formalin is so effective--

DR. RUSSELL: It is going to be very difficult and almost, depending on the amount of residual formalin in the final product, it's almost a non-starter. To do those tests, to look for live organisms in a solution that has residual formalin in it is not a high-productivity venture.

MS. LARSON: Likewise, the contaminant could not have been introduced later in the process? In other words, could it have been contaminated after processing, in shipping or somewhere along the way?

DR. JOHNSON-WINEGAR: You never say never in the biologic world, but I don't thinks--it's very unlikely. The sealing of those vials is pretty good.

CHAIR LASHOF: Let's put it this way. If you have the vaccine and it's formalin and it's got residual formalin, if you try to contaminate it, if someone deliberately tried to put microplasma in, would they be able to get it to grow in it?



DR. RUSSELL: It's unlikely. Perhaps somebody could do something along those lines. Looking for microplasma in these live virus vaccines is a serious and difficult problem and very extensive studies are done to assure the freedom of live virus vaccines. But the formalinized vaccines are intrinsically very, very


CHAIR LASHOF: Thank you very much. That's been very helpful.

Colonel Brundage?

COLONEL BRUNDAGE: Madam Chairman, distinguished Committee members, it is an honor and a privilege for me to share some information with you this morning and to answer your questions.

My name is John Brundage. I'm a physician and an epidemiologist. My specialty is preventive medicine and I'm currently assigned as the Director of the Directorate of Epidemiology and Disease Surveillance of the Army's Center for Health Promotion and Preventive Medicine. The next slide, please.

This rather busy and complicated slide is not presented in order to show you all the small details but rather to present the notion that my subject this morning is one that I consider to be rapidly moving, very dynamic, and one that since the end of the Persian Gulf War has been moving very rapidly and, we think and hope, in the right direction.

To orient you very briefly, there is a time line on the bottom that begins in January of 1992. The events surrounding the Persian Gulf War happened prior to the things that are shown on this slide.

There are two major development processes that are presented on this slide. The first comes down from the top and the second comes up from the bottom. These are the development of what we think is a comprehensive medical surveillance system in the Army that grew out of a previous HIV data system, a large data system that was specifically set up to monitor and track and support epidemiologic analyses of one disease and that was HIV.

Coming up from the bottom was an automated system to provide routine and rapid reporting of diseases, events, or outbreaks of particular preventive medicine or public health interest.

These two systems were developed and

merged in 1995 and the acronym DMED, which is in the center of the line that is proceeding forward now, stands for Defense Medical Epidemiology Data Bases, and I will be talking about that later. The next slide, please.

The Army medical surveillance activity, which is operated out of my directorate, stores personnel and medical event data from multiple Army and DoD sources. It maintains data and longitudinal files. That is, information on soldiers in the reserve and active components are kept in files that document over the entire course of a soldier's career medical events and other events related to their service.

It is an integrated, rapidly accessible system. It links personnel data to presumed highrisk exposures, such as participation in various deployments, and also medical events. It is capable of delivering routine and special reports and it produces tailored data sets and analyses to support operational and research needs. The next slide, please.

MR. CAPLAN: Excuse me one second. Is

that computerized?


There are various applications of this overall data system, and I will talk about three very briefly this morning because I think they are most relevant to the topic that we are talking about.

The reportable disease surveillance system, again, it is an automated system for notifiable disease collection. There are over 100 events, mostly infectious diseases, that are required to be reported, just as a public health department in the civilian community requires reporting from care practitioners of certain diseases or events of public health or operational importance. In the Army, one of these reportable events are vaccine adverse reactions.

This system allows for consistent data coding and data entry. There is reliable data transmission, so that reporting to a central place worldwide by electronic means. Case reports are managed locally. There are daily, weekly, and monthly reports that are generated by the system, and just to give you an idea of the scope of this system, in calendar year 1995 in the Army, there were 7,710 reports from medical treatment facilities Army-wide. The next slide, please.

For hospitalization surveillance, the Army

medical surveillance activity receives monthly updates of all hospitalizations for all active duty members. It receives on a weekly basis, beginning with the current deployment in Bosnia, records of all hospitalizations that occur at field hospitals or fixed facilities in Europe or elsewhere, so that on a weekly basis through a system that is called PARRTS, we receive records of all hospitalizations that occur during the deployment. This allows for up-to-date tracking of hospitalization dates and of non-effective rates. The next slide, please.

The third system that I just would like to quickly summarize is a deployment surveillance system. We receive rosters of individuals who are participants in deployments for all major deployments, and the Bosnia deployment, for instance, is one of those.

This system links deployment cohorts, that is, individuals who are known to be deployed, with medical event data, and that medical event data can be either data that occurs during the deployment or data that occurs following the deployment. This allows for comparisons of experiences of deployment groups with matched control groups.

So, for instance, this system allows very quickly assessments of questions like, were people who participated in deployments to, let's say, Somalia or Haiti or Bosnia, for the year following their return, did they have any different experience with regards to a particular diagnosis that would result in a hospitalization, in comparison to a group of soldiers who are like them in many ways, and those ways could be gender, ethnicity, military occupational specialty, age, or so on, with regards to that same event?

This system allows very rapid answering of those kinds of questions and it also allows us prospectively to look for some differences between

deployment groups and groups that are like them in other ways but not deployed so that we can do proactive, prospective medical surveillance postdeployment.

The other thing about this system is it does form a link to the Army/Navy Serum Repository, which has an acronym of ANSR, which is an archive of serum that is routinely collected, stored, and kept in a frozen state. The next slide, please.

The Defense Medical Epidemiology Database,

which we call DMED, is a data system that Dr. Johnson-Winegar mentioned previously. It is resourced under the Defense Women's Health Research Program. The DMED integrates Army, Air Force, and Navy epidemiologic capabilities.

It defines standard methodologies and standard data elements among the services and it will provide Internet access to reports and data through a defense medical epidemiology network. So some of the things that I have been talking about that we currently have working in the Army will be working tri-service when this system is completed. The next slide, please.

This is a schematic of what the DMED and the defense medical epidemiology network will look like. It will, if you will, be a virtual triservice defense epidemiology data system. On the right is the Army system that I have been talking about in Washington, D.C. At the bottom of the slide is an Air Force epidemiology data system in San Antonio, Texas. On the left is a Navy system at the Navy Health Research Center in San Diego, California.

Through this process, those three data systems will be tied together electronically and authorized users will have access to standard data from any of the services or all the services, either through a hard wire, that is, people who are actually at the place, or through Internet type of access. So this is a system that has been designed and is being developed. We expect that within a year or two, that we will have at least a pilot site that will provide this kind of access for doing epidemiologic studies. The next slide, please.

This is just a summary to try to give you an idea as to the scope of the Army medical surveillance activity. These data are currently stored on-line and they are all linked together in a data system and related together so that questions can be responded to very quickly, answering data from these different data sources.

There are records for over three million

soldiers in the active and reserve components and there are about 34 million records that document demographic information for those soldiers. So as an individual goes through, if a demographic piece of information changes, for instance, the individual changes marital status or military occupational specialty, that would cause a record to be established in this system. There are 8.6 million, approximately, serum samples that are archived that relate to these individuals.

Applicants for military service, all

individuals who are civilians and applying for military service have a record that is established

in the system. So as a civilian crosses the threshold from civilian to military life, there is established a record that would allow, if required, to track that individual from that time. The next slide, please.

These are some of the medical events that are currently stored in this data system. Active duty Army hospitalizations, there are records documenting more than 880,000 of those hospitalizations with discharge diagnoses and procedure codes.

Reportable diseases, the automated disease reporting system that I mentioned, there are more than 15,000 reports in that system, and the total banked serum in the Army/Navy Serum Repository is more than 17 million specimens currently.

Another part of information that is

currently in that system are health risk appraisals, or HRAs. These are reports that individuals in the Army fill out at various times, when they go for physical exams, for instance, and they report various behaviors or conditions that relate to their risk and those are documented in the system, also. The next slide, please.

This completes the summary that I wanted to present to you this morning. If there are questions that I can answer, I would be happy to try to answer them now.

CHAIR LASHOF: Thank you very much.

This is, as you said, an evolving system.

The design of following a cohort deployed and nondeployed and comparing them, how big will those cohorts be? You are not going to try to follow all--I am not sure I got a clear picture of what percentage factors and what size cohort and the time frame in which that part will be operational.

COLONEL BRUNDAGE: The design of the

system now is to systematically and routinely track all individuals while they are in military service. During that period of time, they have certain exposures, in an epidemiologic sense, of interest. Some of those exposures of particular interest are participation in certain deployments.

When there is a deployment, there is established a separate data base that documents the date that the individual was deployed and the date that the individual returned from the deployment. Those data are integrated into this system.

So, for instance, we could go back to 1992 and we could say, in 1992, of all the people that were in the Army, of the ones since then who deployed to Somalia, Haiti, and Bosnia, did those individuals have a different experience with regards to hospitalizations or reportable conditions as compared to people who were in the service in 1992 who did not participate in those deployments?

So the answer to your question is, right now, every deployment that is considered at this point to be a major deployment, and that decision is made at the Department of Defense level, is integrated into this system and individuals who experience those deployments have that tracked in the system.

CHAIR LASHOF: So for hospitalizations, at least, you would have it on everybody? It is not a

sample, it is not a cohort?

COLONEL BRUNDAGE: That's right, yes. CHAIR LASHOF: What about for following up

for non-hospitalization illnesses?

COLONEL BRUNDAGE: The system that I'm describing now is, I think, a very powerful system, but the requirement to use the system and to add to the system is to have a data base that is in electronic form.


COLONEL BRUNDAGE: Right now, hospitalizations are recorded in an automated system and we receive those in electronic form. Outpatient experiences right now are not routinely documented in electronic form. They're documented on paper. So when outpatient experiences are in automated form, when we have an outpatient system that is automated, at that time, that will be included in the system and we will be able to say things about outpatient experience. Right now, the only thing we have that documents outpatient experience are things that are considered to be reportable in and of themselves.

CHAIR LASHOF: So basically, the system you're describing to us and that you're planning at this point to make operational, is one that deals with everybody--


CHAIR LASHOF: --and is based on how fast you can get different records automated?


CHAIR LASHOF: You have not, at this point, designed an ongoing system where you might have a cohort population, a sample population that you would follow and collect additional data on, like a five percent sample of everyone that was deployed, randomly, you would pick them out and follow them up afterwards with periodic questionnaires or other follows and then an equal five percent match who weren't deployed that you might send questionnaires to every six months to say, how are you doing, fellow?

COLONEL BRUNDAGE: That is not something that we do routinely. There are things like that that occur on an ad hoc basis.

CHAIR LASHOF: Are you discussing the feasibility of doing the kind of cohort issue I am talking about?

COLONEL BRUNDAGE: Yes, ma'am. What I was describing to you this morning, I think, is what we are doing routinely and systematically all the time. Outside of that, we do plan and discuss and execute studies like you're talking about, where we identify a specific, unique threat and then plan an ad hoc, if you will, more focused and more complete surveillance of that group when they enter a relatively high-risk situation and come back from that.

An example, I think, is Bosnia. There was a detailed surveillance plan that was produced for Bosnia that does have integrated into it some special studies that are done for soldiers who participate in that and then return from that.

CHAIR LASHOF: The other question, which

maybe you can't answer and is a low-ball one, we have heard some horrendous problems with records,

of records being lost, data not being in records, and so on. What kind of quality control system are you building into this one that you will really be on top of these records and not faced with what we have been hearing?

COLONEL BRUNDAGE: I am trying to decide whether to try to give you kind of my personal feeling or kind of a general response.


COLONEL BRUNDAGE: I will give you my personal view of this. I am very proud, and I think we have come an incredibly long way in all of these areas from the time of the Gulf War until now. That includes everything from the interest and the priority that now is being devoted to this kind of effort. That includes completeness of record keeping, or at least emphasis on complete record keeping and emphasis on quality of record keeping. We still have a long way to go, and we have a long way to go with regards to record keeping, particularly in regards to outpatient experiences and those kinds of things.

With regard to the things that we have now, we routinely do, for instance, quality control that is built into putting records into this system, so that we have, for instance, edit checks that do not allow pieces of information that fall out of certain kinds of ranges to be put into the system. We look for missing values for certain things. So we do routine editing to assess the completeness and the accuracy of the data that is coming into the system, but we still do have significant problems, I think, with records that are kept on paper.

CHAIR LASHOF: Thank you very much. Questions? Elaine?

MS. LARSON: Just for clarification, what information, if any, do you have on Gulf-deployed people in the system now?

COLONEL BRUNDAGE: In the system now? We have a record in the system of all individuals who participated in that deployment. So all veterans of the Gulf War, a record is included in that system.

MS. LARSON: That they were there? Do you have their hospitalizations?


hospitalizations during and following that deployment, if that hospitalization occurred in an Army medical treatment facility.

MS. LARSON: And anything else? Do you have anything else?

COLONEL BRUNDAGE: As long as those

individuals stay on active duty, we have, for instance, whether they participated in other kinds of deployments. We have, for instance, a record if they had one of those conditions we consider to be reportable and if that was identified and reported. We have changes, for instance, in demographic information, so if they got promoted, if they changed their occupational specialty, if they changed marital status and things like that.

MS. LARSON: So if Gulf participants are still on active duty, you have them fully up in this system?


MS. LARSON: So there are data there that are possible to use. What happens when people retire and go into the VA system? What is your plan for the data then?

COLONEL BRUNDAGE: Right now, this system does not link with veterans systems.

MS. LARSON: What is your interaction, if any, with this data base or your plan for it with the medical follow-up study of the Institute of Medicine?

COLONEL BRUNDAGE: Right now, we do not have a plan to link these data with that study, from this system.

MS. LARSON: Why not?

COLONEL BRUNDAGE: As I said, this data system draws data that are currently collected and maintained in other data sources. So the data that are in this system come from a number of other data systems that are set up to support a lot of other applications. So these same data that are now integrated in this system have been used extensively to support a number of Gulf War veteran studies.

Data that are in this system--the value added to the data of this system is that they are stored and integrated and they are already on-line and they are routinely updated and ready to go to support epidemiologic studies.

MS. LARSON: So it is a repeat of data that are other places and there is nothing in there that wouldn't be found somewhere else, but eventually, you would hope--I mean, one would hope, I guess, that you wouldn't be having a number of data collection systems, that there would be one?



MR. CAPLAN: Colonel, I wonder if you could tell me a little about how big your surveillance team is. I mean, how many people are working there? How large is this group?

COLONEL BRUNDAGE: We have about 14 or 15 individuals full time who are working at this center.

MR. CAPLAN: Are you able to conduct any kind of audit in the field, aside from what you get in editing, before you enter data into the computer, do you have any quality control that goes out into sites, big sites where you might be getting lots of data from in terms of quality control?

COLONEL BRUNDAGE: For each of these data sources, we have different ways of tracking back to assess the quality of the data. For instance, the reportable disease data that I was telling you about, those data are reported every day into our system. We review those data every day. We look for data and routinely check back to the reporting site to say, this was an unusual thing. Did you really diagnose this?

So for those particular instances, for instance, we check every day back to the reporting place to check on the accuracy of the report and the implications of the report. So the answer is yes, and that's just an example of how we do it.

MR. CAPLAN: And if you were going to

enter people in today who were coming in through

the reserves or active military, is there a standardized physical that they would get, both for entry into the Guard or the reserves or active duty that you would be able to say is a uniform baseline to enter into the system?

COLONEL BRUNDAGE: There is not a physical exam record that goes into this system.

MR. CAPLAN: What would it take if we were to suggest in our recommendations an in-depth study of a small subcohort so that they could, if you will, be used as a monitor, a kind of ongoing baseline, pre-deployment, given the resources you've got, to come up to speed to be able to say that, oh, I do not know, one percent of Guard and reserves had an in-depth standardized physical assessment, serum deposits, and all the rest of it, and then we would look to see later what happened, a post-deployment follow-up?

In other words, one of the things I think the Committee, or at least me, has been flirting with is the notion of some better deep, in-depth subsample that would give us a good baseline of health status pre-deployment and post- in any large-scale deployment. What sort of resources do you think it would take to expand what you do from a general epidemiological overview of what is going on day-to-day in hospitals and with accidents and so on into that kind of area? That is why I was asking you how many people you had. If you were writing a grant proposal, let's say.

COLONEL BRUNDAGE: I would have a hard time off the top of my head. I would have to start with--

MR. CAPLAN: Would it be fair to say you can't do it now with what you've got?

COLONEL BRUNDAGE: That's true, and I think that the problem now is that something like that, I think, would have to be added on to the people that are there now, because particularly during a time of deployment, that is a particularly busy time and I just think it would be--

MR. CAPLAN: We've heard testimony here that it's hard to get--when you're rushing to get people out there, the last thing you want to do is, of necessity, be kind of engaged in this deeper baseline information, and we heard also that when you're trying to pull out from a deployment, when things are over, people don't want to hang around and have in-depth physicals. They want to go home.

That's why I'm fishing around here to see

what we could be doing in terms of being ready before we're in a crisis mode and then being ready when we're in a party mode, assuming things turned out well and we're pulling back.

One other question. Of the 15 million tissue samples that you've got, what is the informed consent for their use and storage? Do you destroy them when people muster out? What is the status of the bank there?

COLONEL BRUNDAGE: The specimens are archived with a specimen number and not a personal identifier. People cannot go into that serum archive, for instance, and find a specimen that belongs to an individual. It has a specimen number that can only be linked to an individual through a data system, which is the system that we maintain.

Those serum are not provided to individuals to be used, for instance, to look for antibodies or anything else without a documentation of the plan or the protocol that clearly explains what the use is. That, then, has to go through the appropriate institutional reviews to make sure that that intended use meets human use standards, for instance.

When the intended use has been reviewed and approved, then we get involved and then we're able to draw serum and turn that over to an authorized investigator, who then is required to only use those sera for that intended use.

MR. CAPLAN: But now you've got a largescale serum registry--


MR. CAPLAN: --non-identified information, all identifiers out--

COLONEL BRUNDAGE: That's correct.

MR. CAPLAN: So in a way, it wouldn't be quite useful for the sort of thing I'm talking about in the abstract here about being able to preand post-sera analysis on who went where, trying to follow them out in-depth, unless you had a special protocol to do that?

COLONEL BRUNDAGE: If there's a special protocol that says, for everybody who participated in a certain deployment, can you retrieve a serum specimen prior to the date of deployment, can you draw a serum specimen after the deployment, and can you turn that over to a group of investigators who would want to see if there is a change in antibodies, yes, we do do that. That is one of the main potential applications of this archive.

MR. CAPLAN: So it could be done. It just requires the usual applications and reviews?


MS. TAYLOR: You mentioned the outpatient experiences are being brought into the database. Is that being done now, or is this something that is being planned?

COLONEL BRUNDAGE: Outpatient medical contacts now are not routinely--

MS. TAYLOR: Brought into the system. COLONEL BRUNDAGE: --automated.

MS. TAYLOR: Right.

COLONEL BRUNDAGE: There are some systems that are being developed. They are being piloted at some outpatient clinics. So there are plans to do that. It is more than just plans. There are actually some outpatient medical records that are being tested as we speak, and assuming that that goes very well and it is at some point in the future implemented DoD-wide or Army-wide, at that point, we will be able to put it into the system.

ADMIRAL CUSTIS: You are referencing the

automated clinical record, are you not?


ADMIRAL CUSTIS: Will the time ever come when there will be a military-VA coalition of effort in that regard? Will an automated clinical record be commonly used in VA facilities, do you think?

COLONEL BRUNDAGE: Sir, I don't think I could speak with much authority about that. I don't know.

ADMIRAL CUSTIS: I think Dr. Murphy is back there shaking her head. Is that a yes or a no?

DR. MURPHY: There are some efforts underway, sir, through the reorganization in government, through REGO II, looking at ways for the VA and DoD to cooperate on joint systems. VA and DoD are exploring a means to improve and ensure compatibility of medical information systems. These efforts are currently ongoing.

CHAIR LASHOF: Does anyone else have any more questions? If not, thank you very much. This has been very helpful, indeed.

We will recess for lunch and resume here at one o'clock.

[Luncheon recess.]

A F T E R N O O N S E S S I O N CHAIR LASHOF: I think we will go ahead

and get started. Colonel and Danley and Dr. Johnson-Winegar--you are going to get to be an expert here--thank you very much for joining us today. I believe, Lieutenant Colonel Danley, you are going to start?


CHAIR LASHOF: You are going to start. Go ahead.


DR. JOHNSON-WINEGAR: Again, Madam Chairperson and Committee members, thank you for the opportunity to make a presentation to you this afternoon. My colleague, Lieutenant Colonel Danley, and I will be sort of splitting this presentation and his comments will be interjected amongst mine. Of course, if you have specific questions as you go along, we can answer them then or we can wait until the end, whatever seems to be the most appropriate.

The subject of our comments this afternoon relates to the development of drugs and vaccines for prophylactic use against chemical and biological warfare agents. The next slide, please.

The Committee request was broken into

various subsections and it is our intent to address those in the order that they were presented to us. As I have indicated, Lieutenant Colonel Danley is representing the Joint Program Office for Biological Defense, and I, as the Director for Medical, Chemical, and Biological Defense, am representing the U.S. Army Medical Research and Materiel Command of which USAMMDA is one of the subordinate activities.

The first specific question relates to efforts to obtain approval licensure of investigational drugs and vaccines that were used during the Gulf War conflict, specifically botulinum toxoid vaccine and pyridostigmine, and I will go through each of those in a chronological fashion to give you an update of our efforts to date.

Beginning first with the pyridostigmine bromide, beginning certainly prior to 1992, we have had ongoing discussions with the FDA, but I chose to start the chronological listing here simply for the sake of time and for summary. We have had a number of issues to discuss and the theme that you will find running through this presentation

essentially relates to the fact shown here in the second bullet, in that we cannot do clinical efficacy trials for our products, our medical products that we have developed to protect against chemical and biological warfare agents.

We are having ongoing, active discussions with the FDA to resolve that issue and I will be discussing some of that in my comments, and in the subsequent comments from the FDA personnel later this afternoon, I think you will hear additional testimony regarding that.

Basically, in March of 1994, the Army did file a new drug application for pyridostigmine with the FDA. That application was not accepted because the sections on chemistry, manufacturing controls, were not acceptable to the FDA, but they did agree to review the remaining sections of the document. The next slide, please.

What we consider a pivotal study was conducted. Some animal studies were done at the Battelle Institute in Ohio. The FDA did conduct a complete audit of those pivotal animal studies and found them to be acceptable.

I won't go through each of the specific actions listed on this chart, again, for the interest of time, but I think that you will see that we have come to the final resolution in that after a number of meetings to discuss the issue of surrogate markers, which I will come back to later in my comments, we have agreed that the FDA will consider the animal studies that we have in lieu of human clinical efficacy studies. Our current time line projects us to be filing a new drug application for pyridostigmine bromide in early May of this year.

MR. BALDESCHWIELER: Excuse me. I thought the drug was already approved for at least one other indication.

DR. JOHNSON-WINEGAR: The drug is approved for a different use.

MR. BALDESCHWIELER: So you have to go back through the CMC sections to get approval for a different indication?

DR. JOHNSON-WINEGAR: Yes. It is an entirely new application.

Again, summarizing some of the barriers and the concerns that we have regarding the fielding of pyridostigmine bromide, first, as you are well aware, clinical efficacy trials cannot be conducted in humans for both legal and ethical reasons. In order to resolve that issue, we have proposed use of a surrogate endpoint in order to measure the efficacy of this particular compound, which is a pretreatment.

The normal new drug application approval process does not fit military-use items, specifically because of the requirement to do human efficacy trials.

A final issue that is perhaps more generic to medical, chemical, and biological defense compounds is one related to indemnification. The point that I would like to make here is that the manufacturers from the private commercial sector are quite concerned about their liability for the use of these products and we have had some difficulties in finding commercial partners for our

products. Their main concern, again, is what is their legal responsibility.

In this particular case, Roche Products, who is the manufacturer of our PB, has requested indemnification from the government and that requires approval all the way at the level of the Under Secretary of Defense for Acquisition and Technology, and that particular application is being processed right now. The next slide, please.

With regard to the botulinum toxoid, again

this was used as an investigational new drug during the Gulf War. We have lots one through four. We have manufactured some new lots to obtain some consistency data. We are in the process now of collecting additional safety and immunogenicity data for this pentavalent toxoid under an IND that is sponsored by the CDC. The next slide, please.

MR. BALDESCHWIELER: When you say "we",

who is literally filing the IND?

DR. JOHNSON-WINEGAR: The current IND is held by the CDC and we are conducting our studies and filing it under their IND. We have a protocol for contingency use in times of military contingencies, but for our normal at-risk populations in laboratory workers or for specific protocols, we are using their IND.

MR. BALDESCHWIELER: And the processing site of this is done where? Who is the vendor?

DR. JOHNSON-WINEGAR: This is done by the

formerly Michigan Department of Public Health, now the Michigan Biologic Products Institute in Lansing, Michigan, the same manufacturer as for the anthrax vaccine.


supplying the process outside of the application? DR. JOHNSON-WINEGAR: Yes, that's correct. Specifically, what we are doing with

regard to the botulinum toxoid is we are continuing to conduct some booster studies. I summarized those for you in my presentation this morning with regard to some Gulf War veterans who were volunteers in a study to look at long-term immunogenicity of this product.

We are continuing to have ongoing

discussions with the FDA in regard to licensure of this product. As I just mentioned, we do have a contingency protocol. Should we need to use this product again in the very near future, we would do that with informed consent and that protocol has been submitted to the FDA for their review.

With regard to getting this product

licensed, we have proposed at a pre-meeting with the FDA held just two weeks ago, we plan to do surrogate animal efficacy studies for all five serotypes of botulinum toxoid.

For those of you who are not real familiar with the terminology there, there are five different types that do not cross-react or crossprotect from each other. So, in essence, this could be called a multivalent vaccine or a combination vaccine, because, in essence, it is five individual toxoids that are combined into one pentavalent product. We plan to test each of those types separately to show that, in fact, the pentavalent product does protect against types A, B, C, D, and E of botulinum toxoid.

We will continue to do Phase I and II studies in humans of all manufactured lots. Phase I will be safety studies and Phase II are immunogenicity studies, where we will measure the serum antibody response to the toxoid in volunteers. We will continue to do storage and stability testing of the lots of pentavalent toxoid that have already been manufactured.

We will prepare and submit a product license application and an establishment license application for the botulinum pentavalent toxoid. The next slide, please.

Again, the barriers and the concerns that we have, acceptance of the surrogate animal efficacy studies versus human efficacy studies. This is a major point to be discussed. There are a number of different ways that the studies can be done. We think that for the botulinum toxoid, it is a relatively straightforward one in that the ability to measure neutralizing antibody in the animals that have been vaccinated and then challenge those animals with deliberate exposure to the toxin, and then subsequently to be able to relate a corresponding level of antibody in humans that have been vaccinated with the product, we should, therefore, be able to make the conclusion that that same level of neutralizing antibody would be protective.

We are also considering doing passive transfer studies, where serum from vaccinated individuals would be passively transferred into animals and then the animals would be subsequently exposed to the toxin, thereby demonstrating that the particular characteristics of the human antibody are equally protective.

Another concern that we have in this particular case is that the DoD remains dependent on the manufacturer because the manufacturer will hold the product license as well as the establishment license. In this particular case, an establishment license for this product is going to be a little bit tricky to address because the product is no longer produced using the same technologies that it was at that time.

MR. BALDESCHWIELER: Is this produced in horses?

DR. JOHNSON-WINEGAR: No, sir. The product produced in horses is an antitoxin that can be used for treatment. This product is produced by culturing the bacteria and then purifying the toxin from the culture supernatant and then inactivating the toxin with formaldehyde so that it is an inactivated vaccine that retains its immunogenicity but has lost its toxicity.

The second question that we were asked to address, what other products are of priority interest to us? We interpreted that to mean products beyond anthrax vaccine, botulinum toxoid, and pyridostigmine bromide.

With regard to biological products, the first one that I have up here is anthrax vaccine relicensing. We are currently undertaking an effort to reevaluate the immunization schedule for anthrax vaccine, realizing that the currentlyapproved licensed regime consists of six immunizations, the first three being given at two-

week intervals, the second three being given at six-month intervals, and a subsequent requirement, then, for an annual booster. We hope to be able to obtain sufficient data to recommend a reduced number of immunizations.

The pentavalent botulinum toxoid, I just described to you. In addition to that, there are two other serotypes, types F and G. We have development efforts underway. Again, these will be made by conventional methods of growing the bacteria, isolating the toxin, and inactivating the toxin through conventional methods.

The product that you referred to just a moment ago, the one that's made from horses, is an immune globulin product that is despeciated and only the F(ab')2 fragments are used to reduce the potential for serum sickness. That is a heptavalent product containing antibodies to all seven types of the botulinum toxin. That would be used primarily as a treatment. The next slide, please.

Other products in our medical biological defense program that are in advance development include a live attenuated vaccine for Tularemia, a toxoid for Ricin, a cell-cultured vaccinia virus vaccine intended to replace the old smallpox vaccine, and a vaccine for Q fever that is a chloroform ethanol residue extract.

Continuing with additional medical biological defense products, a recombinant vaccine for Venezuelan equine encephalitis, a toxoid for staphococcus anaratoxin B, both a traditional toxoid and a recombinant vaccine, and we also have an effort underway to develop specific diagnostic kits for exposure to biological warfare agents.

With regard to products for chemical

defense, we have already discussed the pretreatment pyridostigmine bromide. We are also developing topical skin protectants, a multi-chambered autoinjector for nerve agents, and a pretreatment for cyanide.

Leaving the specific products for a moment, I would like to talk to you just a little bit about how the DoD is organized to undertake the development and approval of these products and specifically what is the role of USAMMDA, that is the U.S. Army Medical Materiel Development Activity.

On this chart that you will see, USAMMDA is responsible for managing the development of all critical medical materiel, not only those for medical, chemical, and biological defense, but across the broad spectrum of naturally occurring infectious diseases and other products and equipment that can be used for treating combat injuries.

You will notice at the bottom here that USAMMDA is the DoD's principal medical materiel developer, and in point of fact, does the development work for all the various armed services. The next slide, please.

A little bit of an organizational chart to show you where the various activities fit. When I introduced myself this morning, I indicated that I work here at the U.S. Army Medical Research and Materiel Command. We are one of the major

subordinate commands that falls under the jurisdiction of the U.S. Army Medical Command and the Surgeon General of the U.S. Army.

Under the U.S. Army Medical Research and Materiel Command is USAMMDA, the organization we were just talking about. Their mission and their role is to be the materiel developer. We also have a logistician who is responsible for the procuring and distribution of a number of medical products. Completing the three-legged approach to how we decide to develop products is what we call our combat developer and that derives from the Army Medical Department Center and School at San Antonio. They primarily develop our requirements and help make the threat assessment.

This chart is a little busy, but it was done deliberately that way to show you the extensive interactions that we have with a number of organizations. Down the center of the chart, you will see reflected again those agencies and organizations that I just told you about.

Centering for a moment here on USAMMDA,

their role in developing various products, you can see that they relate to the joint program office, represented by Colonel Danley, with a number of foreign governments, the Assistant Secretary of the Army for Research, Development, and Acquisition, the Assistant Secretary of Defense for Health Affairs, and within our own organization, the research area directors. That is my current position.

We have a number of subordinate

laboratories that do in-house work. As was mentioned also this morning, we have a contract program where we have efforts both from universities and industry that contribute to our program. And certainly, last but not least is our interaction with the FDA, which will be highlighted further both in my comments and in subsequent testimony to the Committee.

What is the role of the JPO in general? At this point, I will turn the microphone over to Lieutenant Colonel Danley.

COLONEL DANLEY: Madam Chairman, members of the Committee, thank you for this opportunity to address you about the Joint Program Office for Biological Defense. I am Lieutenant Colonel David Danley. I have a Ph.D. degree in microbiology. I have been with the Joint Program Office for the last two years of its three years in existence and I am the Deputy Joint Program Manager for Medical Systems.

The Joint Program Office grew out of a requirement that came from ODSS. We did not have the capacity to either detect biological warfare agents and we did have a shortage of biological defense medical materiel. As a result, the Deputy Secretary of Defense formed the Joint Program Office as a chartered program office to address those two deficiencies. So there are two sides to our office. One is detection of biological agents and the other is the development and procurement of medical biological defense products.

Just to talk a little bit about the acquisition of materiel in the Department of Defense, we walk a very interesting line in our

program office on the medical materiel side because we have to satisfy two sets of requirements. One set of requirements is dictated by the DoD 5000 series, which tells all of the services how to develop products for the Department of Defense. On the other hand, we are also told by the Food and Drug Administration how to develop medical products that are safe and effective.

So our Joint Program Manager, General Doesburg, serves as a Milestone Decision Authority. That is a designation used by the Department of Defense. He has the responsibility for making a decision as to whether a product proceeds in the development process to its ultimate production and fielding. So we can have all the committees that we want making recommendations, but in the Department of Defense, decisions are made by one individual and that individual is General Doesburg.

Because of the importance of this office

and products that are coming out of this office, General Doesburg reports to the Army Acquisition Executive Directly--that is Mr. Decker--who, in turn, reports to the Deputy Under Secretary of Defense for Acquisition and Technology.

This program has a great deal of visibility in the Pentagon right now. While Dr. Johnson-Winegar was explaining to you that the AMEDD Center and School determines the requirements for medical and biological defense products, in reality, there are a lot of other players, particularly in the biological arena.

The Defense Intelligence Agency tells us what the threat is, that is, not what we think the threat is as an individual but what the threat is in terms of potential enemies to the United States of America.

That threat is translated into requirements, and the requirements right now for biological defense products are being examined by the Assistant Secretary of Defense for Health Affairs, by the Assistant Secretary of Defense for Policy, and by the Joint Chiefs of Staff. They are the ones who come down with policy memoranda as to what vaccines we should make, how much we should stockpile, whom we should vaccinate, how often we should vaccinate them. Down at my level in the materiel developer arena, our responsibility is to ensure that safe and effective products are produced.

Clearly, we have a relationship with the U.S. Army Medical Research and Materiel Command. We rely upon them for all of our support, both technical support in their laboratories, program management support through USAMMDA, contracting support, and regulatory affairs support.

The Joint Program Office for Biological Defense has undergone something of an evolution in the last two years. When I first came on board, I was told that my job was to build a vaccine production facility for the Department of Defense, and that sounded like a wonderful thing to do, to build a great big building.

But in reality, what was more important was ensuring that we knew what we were going to make and in what quantities. As we began to look into the process more, we began to realize how

difficult it was to nail down just exactly what it was the Department of Defense was looking for. This is called requirements definition and it is an integral part of developing any kind of system in the Department of Defense.

But we have been very successful at that, and I believe now that our program is evolving into what can be construed as a very productive and, I believe, a very successful program in the future.

Clearly, the Persian Gulf illnesses have

impacted on the way we are doing business right now. You have talked about or heard mentioned the study on the long-terms effect of immunization. Those studies are being funded through our office. Through the milestone process, we are also looking at other issues that we believe could impact upon the administration of vaccines to our U.S. forces.

In addition, we are funding these studies

for the reduced schedule for anthrax vaccine and for getting the botulinum vaccine licensed. Because we are such a small office, we do rely upon MRMC to do the work and we provide the money.

Dr. Johnson-Winegar referred to the number of products that are currently in development that have been discovered in the laboratories of USAMRIID, and I think that is really a remarkable testimony to the technology and the expertise that exists in that facility.

Clearly, there is no commercial application for most of these products. They represent almost orphan drugs and vaccines, as it were. Their purpose is simply to protect U.S. forces. Because they have no commercial application, it is very difficult for us to go out and to find companies that are interested in manufacturing these products for the DoD with the expectation that they are going to return a profit.

As a result, our office has spent a great

deal of effort, particularly within the last year, coming up with what we call the prime systems contract approach. Again, this is an approach very common in the DoD where we bundle products together and go out and find an integrator for the development and production of those products.

What we have discovered, I think, is that making vaccines is a relatively simple process. Mother nature does it for us. We simply grow the organisms and extract the antigens, process them, put them in bottles. The difficult part of making vaccines is the record keeping. It is the testing, the quality assurance and quality control. It is the post-marketing surveillance and following groups of individuals who have received these products to ensure that there are no adverse reactions.

Clearly, with a plethora of vaccines, and when we talk about 18 vaccines in the DoD biodefense program, you are almost talking about the total number of vaccines currently licensed in the United States right now, so this is a very large number of vaccines. Clearly, we need to have an integrator who can ensure that these products are manufactured properly but that everything meets the requirements for FDA licensure of these products.

That licensure process involves two

aspects. One is to demonstrate the safety and

efficacy of the product itself, but also to demonstrate that the facility in which that product is produced meets their standards for production.

When we talk about botulinum vaccine, for

instance, I think it might have gotten lost in the discussion that botulinum vaccine, as a product, is safe and effective. What was missing was the production piece, that constant production year after year after year and the demonstration that we were producing it consistently to enable us to go and get an ELA, an establishment license application.

So we believe that the prime systems contract will help us overcome these barriers which, in the past, have prevented us from getting FDA licensure of all of our products.

That concludes my presentation. Do you have any questions?

CHAIR LASHOF: Thank you very much. Let's open it for questions from the Committee. Andrea?

MS. TAYLOR: I have a question. I don't

know if either one of you can answer this. It's regarding the dosage of either the vaccine or the pyridostigmine bromide tablets. Does every individual receive the same dosage regardless of an individual's size? Is any of that taken into consideration, or other medications that they may be using?

DR. JOHNSON-WINEGAR: Yes. Vaccines are standardized so that there is, essentially, one dose for everybody, regardless of their weight or other characteristics. In the particular case of the anthrax vaccine, it is a half-a-milliliter of the product.

MS. TAYLOR: What about the tablets, the distribution of the tablets? The same?

DR. JOHNSON-WINEGAR: Again, there is no differentiation made for age, sex, weight, whatever.

MS. TAYLOR: Is any synergistic effect known if they are taking other medications from the use of any of those, or particularly the use of the tablets?

DR. JOHNSON-WINEGAR: There's no data that I'm aware of that suggests that the dosage should be changed if an individual is concurrently taking another medication.

MS. TAYLOR: Then my second question is, going back to the tablets again, when you're taking the pyridostigmine bromide tablets, it's my understanding from the testimony that we heard that many of the persons who served in the Gulf were taking them anytime there was an alarm going off. Do we know if a person is taking those and there is no threat of chemical exposure, whether they would have an effect from taking--or adverse health effects from taking the tablets without the threat of a chemical exposure? They are just taking them whenever there is an alarm going off, whether there is an exposure or not an exposure.

DR. JOHNSON-WINEGAR: I think that's exactly the basis for some studies that we are currently conducting.

MS. TAYLOR: So you are conducting studies to determine whether there is?


CHAIR LASHOF: Could you say a little bit more about the studies you are conducting in that regard? On pyridostigmine bromide specifically, is there a way for you to study whether it has a different effect if people are exposed to other different chemicals at the same time, particularly pesticides, in which there might be an interaction or potentiation?

DR. JOHNSON-WINEGAR: Those parameters are not part of the study. The study is specifically designed to include women, because that was not extensively looked at before, and also to do some comparisons regarding body size and duration of taking the PB tablets in the absence of exposure to specific chemical agents.

MS. TAYLOR: That's what is being done now?


CHAIR LASHOF: That is what is being done, but you have no plans to look at the issue of whether one takes pyridostigmine bromide at the same time you are putting pesticides on or taking other medications or any other environmental conditions?

DR. JOHNSON-WINEGAR: No. We have no studies like that planned.

CHAIR LASHOF: Other questions? John? MR. BALDESCHWIELER: What kind of

indemnification can you offer to your prime systems contractor?

COLONEL DANLEY: The issue of indemnification is dictated by the Code of Federal Regulations, that we cannot offer indemnification until after award. What happens after award of the contract is that the contractor is obligated to go out and find or try to find insurance to cover indemnification. He then submits to the Department of Defense, specifically the Army, either the fact that he cannot get insurance or that the cost of the insurance is prohibitive. At that point in time, a decision is made about indemnification.

It has created quite a bit of uneasiness, I think, in potential bidders, but that is what the law states and that is what we have to follow.

MR. BALDESCHWIELER: What about indemnification of the Army materiel acquisition group or whoever is responsible on the Army side?


COLONEL DANLEY: It is covered under the Ferris Doctrine, I believe. That is to say, you can't sue the Army for what happens to you during war. There are some contractors that we have currently making pilot lots of vaccines that are indemnified and we have other manufacturers who have insurance.


ADMIRAL CASSELLS: I just want to nail down one thing, Dr. Johnson-Winegar. Did you say that the FDA had agreed to accept the animal studies for efficacy of the pyridostigmine bromide?

DR. JOHNSON-WINEGAR: No, I did not. If I

left you with that impression, I apologize. What I intended to say was that we have had very productive discussions with the FDA and they have agreed to accept an official filing, and I'm sure--

I won't speak for the FDA, but I'm sure that they will rely upon all sources available to them, be that expert committees or outside reviewers, to help them as they do go through the process of reviewing the data, both for the pyridostigmine bromide and for the botulinum toxoid.

We all agree that this is really a very critical issue for the DoD and for the FDA and I think that we are both going into this with a spirit of being as honest and forthright as we can in reviewing the process and I think that it's been a very cooperative, interactive discussion thus far. No one at this point, I think, is prepared to make any decisions or predictions on what the outcome of that will be.

ADMIRAL CASSELLS: When we went and visited Fort Detrick, we were told that pyridostigmine bromide was likely effective only against Soman and that the use caused some debilitating side effects. In view of that, are there other products or other approaches to pretreatment that you are looking at?

DR. JOHNSON-WINEGAR: Not at this time, no.


DR. PORTER: I have a question for Lieutenant Colonel Danley. Congress mandated the reorganization in the Department of Defense in 1993 to address better issues of biological and chemical defense. Has it fixed anything? Is anything better since that time in regard to what needs to be done?

COLONEL DANLEY: Clearly, the intent of Congress has been enacted by rolling up all defense dollars for chemical and biological defense under the Assistant to the Secretary of Defense for Nuclear, Chemical, and Biological matters. That is Dr. Smith.

I judge that we are in the process, and people always ask me, how long does the process take, and I can't answer that, but we are in the process of changing a culture. We are in the process of, I believe, redefining what a weapon of mass destruction is.

I think ten years ago, if you said a weapon of mass destruction, you would envision an atomic bomb. The fact that chemical and biological weapons represent those kinds of weapons that can be used by relatively unsophisticated countries or terrorists has created a new sense of awareness in the DoD and we are coming to grips with that.

So in answer to your question, I believe the intent of Congress has been enacted. I think the cultural change is ongoing, but as the GAO reported, it is going to take some time to effect that cultural change.

CHAIR LASHOF: Other questions? Joan? DR. PORTER: What is the status of your

prime contractor search? Where are you in that process?

COLONEL DANLEY: The RFP has been completed and is currently being staffed in the Pentagon. It has to be approved by the Chairman of the Strategic Systems Committee before it can be released, and again, when we talk about visibility in the Pentagon, this individual normally gets

involved with B-2 bombers and Seawolf submarines and this contract is nowhere near that kind of procurement action.

But its sensitivity and its importance is such that the Defense Acquisition Board has directed that he review it, so it has to go through quite a few offices before that happens. I hope we will have it out by the end of the month.


DR. PORTER: By the end of-COLONEL DANLEY: By the end of May. DR. PORTER: The end of May?

MAJOR CROSS: Colonel, do you get involved

in equipment, NBC type of equipment?

COLONEL DANLEY: Our office, of course, is involved with the biological detection apparatus, and historically, I have had some personal experience with some medical chemical defense equipment.

MAJOR CROSS: My question would be, what types of new detectors are we looking at currently?

COLONEL DANLEY: There are a number of

different issues in terms of the biological detectors. For the near term, what we will be fielding are basically what we call NDI, nondevelopmental items, or off-the-shelf items. They are air samplers, flow cytometers, the kinds of pieces of equipment that you would find in a laboratory, and we basically put them in the back of a heavy Humvee and train people to look for biological agents in air samples. That is the state of our detection today.

What we are developing are better

samplers, better detectors, and integrated detectors that look at all three types of contamination, that is, NBC. Though we may not see those products fielded until after the turn of the century, they are on the drawing boards, they are being developed, and RFPs are being crafted to get them built.

MAJOR CROSS: Are you working with any of the other services closely in development of this type of equipment? Are they just as interested as the Army is?

COLONEL DANLEY: Absolutely. Absolutely. All three services, and particularly the Navy and the Marine Corps, have a great deal of interest in detecting. We have to kind of consider that each service has their own unique mission and their own unique vulnerability, and when we make a detector and we want it to be a universal detector, because that is exactly what you want, something that can be used by as many groups as possible, we sometimes have to make modifications and go through quite a bit of negotiation to come up with a configuration that each service finds palatable.

But believe me, those negotiations have been going on hot and heavy now for the last two years and I see some very positive movement towards detectors that have common geometry and common supply and equipment. Just put it on a ship in one case, put it in a vehicle in another case, mount it around an air field in a third. That is the strategy on that.

DR. PORTER: I have another question for you, Lieutenant Colonel Danley. You mentioned the

General Accounting Office. They did address the Committee yesterday and noted that in November of 1993, the Department of Defense issued Directive 6205, which required establishment of an immunization plan and policy. Where is that? When is it expected that that implementation plan will actually be issued?

COLONEL DANLEY: There are actually three parts to that immunization plan. The part that is in place right now is the stockpile issue. The Deputy Secretary of Defense has defined what our stockpile of biological defense vaccines will be and that is being implemented, to develop that stockpile.

There is another element that we call the commander's reserve, that is, what sort of extra do we want to the stockpile which commanders could use to support non-DoD personnel that are in the theater of operation. The size of the stockpile has yet to be determined.

The third piece is an annual immunization policy, and that plan is currently being discussed at very high levels within the Pentagon. I wish I had an answer as to when it would be decided upon. We believe it will be decided upon within the next month or so because it is moving in that direction, towards a point of resolution.

I really cannot add anything to the GAO report, however, because they called me and asked me the same question and that's so far up the food chain from where I sit that it gives me a nosebleed looking up.

MS. TAYLOR: Another follow-up question regarding interactions.


MS. TAYLOR: It is my understanding that you mentioned that there are no studies ongoing regarding looking at interactions between the tablets, the pyridostigmine bromide tablets, and other chemicals or pesticides.


MS. TAYLOR: Has that been proposed? Is that being proposed or thought of, that that could be a possibility for research in that area?

DR. JOHNSON-WINEGAR: I am not quite sure I understand.

MS. TAYLOR: Is there an interest to investigate interactions?

DR. JOHNSON-WINEGAR: At this point, there are no specific proposals or studies that have been put forward. I would refer back to this morning's comments and that the DoD is at this point waiting for the Institute of Medicine study to see what kind of recommendations they give us for looking at interactions of drugs and vaccines and that type of thing. Obviously, there are a number of specific things that could be done. It will be a matter of reviewing and deciding what the priorities are and how to put these forward.

CHAIR LASHOF: In that regard, is there interaction between your department and the coordinating board, the Gulf War Coordinating Board, around research priorities, since DoD has put out calls and has set up a group, a working group, a research working group to try to identify priorities? Is your office involved in that?

DR. JOHNSON-WINEGAR: Yes, there is

coordination between those two groups.

CHAIR LASHOF: Another question I have is, are you looking at any other agents as protective against nerve gas besides pyridostigmine bromide? Are there studies of other possible agents that might be used?

DR. JOHNSON-WINEGAR: We have some efforts ongoing in our basic research program to look at things such as scavengers and that type of thing. A lot of the effort there is directed more at treatment rather than pretreatment.

CHAIR LASHOF: Treatment, if there is an all-out nerve gas war, it is pretty acute and pretty fast.

DR. JOHNSON-WINEGAR: That's correct. CHAIR LASHOF: So looking for other things

that might be used in the manner that pyridostigmine has been used would seem to be also an issue.


pyridostigmine alone is not effective. It only really enhances the effect of the treatment, which is the 2-PAM and atropine. So I'm not quite sure I understand. If you're asking, are we looking for a replacement for pyridostigmine, at this time, the answer to that is no.

CHAIR LASHOF: You are satisfied that that is as good as you are going to come up with?

DR. JOHNSON-WINEGAR: At the current time and within the restrictions of the scope of our program, yes.


DR. PORTER: I wanted to ask Dr. JohnsonWinegar about collaborations with other governments.

DR. JOHNSON-WINEGAR: Yes. I had a few more charts that I was going to show.

CHAIR LASHOF: I'm sorry. We didn't mean to cut you off.

DR. JOHNSON-WINEGAR: That's okay. We sort of interrupted the flow there a little bit. They're over there, if we could go to them.

CHAIR LASHOF: I'm sorry. I didn't

realize you were to come back and finish.

DR. JOHNSON-WINEGAR: I did have just a couple of things that I was going to mention on collaborative agreements and interactions with other agencies and other governments.

As you might be aware, a number of our allies are also interested in the same types of medical products for chemical and biological defense and we are certainly an active participant in NATO research study groups to look at these things, as well as materiel standardization groups.

Specifically, there are two groups that

are very active, the Technical Coordination Panel, comprised of representatives from Australia, Canada, the U.K., and the United States, and a second one, which is the Canada, U.K., and U.S. memorandum of understanding. This one covers both medical and non-medical items and we're looking for standardization, again, not only for medical products but also for detectors and a number of other pieces of equipment.

We have a number of defense exchange

agreements that are bilateral on a country-bycountry basis. We have them with Israel, Germany, and a number of other countries. Could you put the next slide up, please?

Specifically in the arena of chemical defense, we currently have over 20 agreements in place with industry to look at specific pharmaceuticals, a lot of area of interest in the topical skin protectants there. I cite just one specific example of an agreement that we have in place with the French to look at some anticonvulsants, and again, a collaborative study with a university, just pointing out the broad scope of our program with industry, foreign governments, and universities.

With regard to the biological defense program, we currently have over 140 agreements in place with industry. A lot of these are materiel transfer agreements where we are testing particular compounds against agents of interest to the military. We have collaborative agreements in place with the CDC to look at filoviruses and orthopox virus. Again, those are viruses that require high levels of biocontainment and the CDC and our laboratory at Fort Detrick are the only ones in the U.S. that have the BL-4 level containment labs.

Finally, an example of collaborative work with a university and another service, in this particular case for some efforts where we are looking at a new plague vaccine.

The next chart, again, is a repeat of one that I showed you before, but it does, again, just sort of summarizes for you the fact that the DoD, specifically the Army, since the Army has been designated as the executive agent for all the DoD, interacts on a continual basis and a very cooperative proactive basis, not only with other agencies within the Federal Government but with foreign governments, with the private sector, universities, with industry, and with the FDA.

I had just two more charts, if you could just skip that one. Again, just summarizing what our efforts are, concentrating on, at the moment, summarizing again for you our primary emphasis on getting our products fully licensed and approved by the FDA. It hinges on the fact that we cannot do traditional efficacy studies for our drugs and our vaccines, that the filing requirements are not the same, and the indemnification issue, which we already discussed.

My final slide indicates support for the comment that was made earlier in response to one of your questions. I think that the oversight and the visibility for both our chemical and biological defense programs has been substantially elevated since the Gulf War.

I think that our program all the way through, from our basic research programs through our development process and into the acquisition and procurement arena, is a comprehensive one. It is a proactive one. It is a very positive one in which we are able to leverage other Federal agencies. We are working with the industrial and academic sector to the best of our abilities.

We are definitely coordinating with our

other allies, and there are some very active discussions ongoing there.

Our discussions and interactions with the FDA have certainly been on a very positive note as we both struggle with a number of these issues that are critical to all of us.

Finally, I think that the program as it is structured today does respond both to serviceunique requirements and to those that are generic to all of the armed services.

Thank you for the opportunity to present those last charts.

CHAIR LASHOF: Thank you very much.

Are there any further questions that we didn't cover before, if anything else has come up? If not, again, thank you for your presentations.

Dr. Nightingale?


DR. NIGHTINGALE: Thank you. I am Dr. Stuart Nightingale, the Associate Commissioner for Health Affairs at the Food and Drug Administration. With me today, actually, almost with me today is Dr. Robert Temple, who is Director of our Office of Drug Evaluation I, Center for Drug Evaluation and Research, who should be here momentarily. He is at an important FDA advisory committee and wanted to respond to your request for him to be here and promised he would be here as close to two o'clock as possible.

Also with me today is Dr. Karen Goldenthal, who is our Director of the Division of Vaccine and Related Product Applications, the Center for Biologics Evaluation and Research.

I am pleased to be able to address the Committee on FDA's new drug and biologic approval process in general and as it relates to the approval of drugs and biologics that might be used to counter chemical and biological warfare agents. Per your request, I will discuss the accelerated approval process as one of the approaches for new drug and biologic approval and its relevance to this area.

As the Committee is well aware, during the Persian Gulf War, FDA authorized the use of two investigational products, botulinum toxoid and pyridostigmine bromide, for use as prophylaxis treatment. DoD requested the assistance of FDA in allowing the use of these products in certain battlefield or combat-related situations in which they considered obtaining informed consent not feasible. It should be appreciated that FDA appropriately gave considerable deference to the Department of Defense's judgment and expertise regarding the feasibility of obtaining informed consent under battlefield conditions.

I had the pleasure of appearing before your panel on the use of investigational drugs and vaccines in the Gulf War, chaired by Dr. Caplan, in January, and provided testimony that explained why the informed consent waiver process was utilized and the judgments that went into the approval of these products for use in that narrow, time-limited military combat situation.

On behalf of FDA, I would like to thank the Committee for its helpful comments in its February 15 interim report. FDA has begun to take

steps to develop a Federal Register proposal and will seek public comment, especially on topics that you have suggested that we consider in any further proposal on this topic.

You also made it clear in your interim report that you would be looking at the approval process, and we have begun to review internally our own policies and procedures for approval of these types of products. It stands to reason that it is better to use approved products, where feasible, and not to have to deal with investigational products with or without informed consent procedures in military combat situations. FDA, of course, would approve these products and others should the products be able to meet the statutory requirements for approval.

We will not be able to give you any final answers on our views today because it is still an issue that we are considering within FDA and is very dependent on issues of science and law. However, in responding to the questions that you have addressed to FDA in your letter of invitation, we believe that you will see some of the problem areas more clearly and understand some of our current thinking.

Suffice it to say that the accelerated approval process issue is one that is under active discussion within the agency, not just for prophylaxis treatment for chemical and biological warfare agents but also for its relevance to the approval of antidotes and related products in general.

I will now describe the statutory basis for and procedures used in new product approval. In so doing, I will deal with some of the questions raised in your letter of invitation.

The legal standards for effectiveness and safety for the approval of drugs and biologics, including vaccines, are set forth in the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act. Substantial evidence of effectiveness, as determined from adequate and well-controlled studies, and appropriate assessment and demonstration of safety for each specific indication or indications must be shown.

The Center for Drug Evaluation and Research, CDER, and the Center for Biologics Evaluation and Research, CBER, evaluate and approve new drugs and biologics for marketing on the basis of safety and effectiveness and also assure that these drugs are properly labeled.

The drug development and approval process involves two stages. Both drugs and biologics have an investigational new drug or IND stage, and drugs then have the new drug application, NDA stage, while biologics then has a product license application, or PLA, and an establishment license application, or ELA, stage.

Before a new drug or biologic may be tested in humans, the drug's or biologic's sponsor must file an IND. The IND contains the drug's structural formula, composition, information about manufacturing processes, the results of animal testing, the proposed protocol for clinical testing in humans, and other data.

The Center have used the IND to determine

whether the data are sufficient to initiate clinical trials. An IND becomes effective, that is, the study can proceed, 30 days after filing, although the agency may place the IND on clinical hold, usually because of safety concerns.

The Center monitors the clinical trials performed under the IND. When the trials are complete and the manufacturer believes that there is sufficient evidence of safety and effectiveness, the manufacturer files an NDA or PLA-ELA, which must contain full information about the proposed product, including the comprehensive and detailed results of clinical testing. An inspection of the manufacturing facility may be performed, as well.

FDA reviews the submitted data to

determine whether the drug or biologic is safe and effective and properly labeled, and if it is, approves the application. The drug may then be marketed. The manufacturer must continue to send FDA periodic reports and other related reports on adverse reactions and other aspects of drug or biologic experience. Periodic inspections are also performed. FDA may require changes of labeling or take other actions because of problems that are revealed in this way.

Each IND, NDA, or PLA is reviewed

internally by teams of FDA scientists, including physicians, pharmacologists, chemists, pharmacokineticists, biometricians, biologists, and for some products, microbiologists. The agency usually will present important NDAs or PLAs to advisory committees, whose recommendations are valued, although not binding on the agency.

If a manufacturer wants to claim a new use for a drug or a biologic with an approved NDA or PLA, a supplemental NDA or PLA needs to be filed and approved.

Before biologics, such as a new vaccine or allergenic, can be marketed, the manufacturer must send the Center test data that demonstrate that the product is safe and effective and the Center must license the product, in contrast to approving an NDA for a drug product, as well as the establishment producing the product. For some products, the Center may also test some lots to assess whether the standards are met.

I will now turn to our accelerated

approval process. FDA's accelerated approval process permits approval of a drug or a biologic agent based on adequate and well-controlled clinical trials establishing its effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity.

It applies to new drugs and biological products intended for serious or life-threatening illnesses that provide meaningful therapeutic benefits not available through existing therapy. The procedure is coupled with requirements committing the sponsor to post-marketing studies to establish and define the product's clinical benefit, where this is necessary.

The accelerated approval procedure

provides that if the agency concludes that a

product shown to be effective can be safely used only if distribution or use is restricted, the agency will require such post-marketing restrictions as are needed for safe use of the product, such as restricting distribution to certain facilities or physicians with special training and experience.

The procedure also includes a streamlined procedure for withdrawing approvals under certain circumstances, including if the post-marketing studies fail to verify clinical benefit.

I will now turn to the approval of drugs and biologics intended for prophylaxis or treatment for chemical and biological warfare agents. The same legal standards for approval for drugs and biologics apply to products intended for prophylaxis or treatment for chemical and biological warfare agents.

However, there are major difficulties in conducting prospectively controlled clinical trials to demonstrate effectiveness directly because of the low incidence of the disease or condition and the ethical problems that would arise in exposing patients to chemical and biological agents. It, therefore, may be necessary to consider other sources of clinical data, such as use of data collected from accidental exposure. Additional studies can include immunogenicity studies or possibly non-clinical studies in animals.

I will now turn to the relevance of the accelerated approval process to these products. The accelerated approval mechanism suggests a possible approach to dealing with the inability to carry out controlled studies of drugs and biologics intended for prophylaxis or treatment for chemical and biological warfare antidotes.

While this mechanism may be helpful, its applicability must be assessed on a product-byproduct basis. It should be noted that this mechanism bases approval on a reasonable surrogate marker of effectiveness on condition that studies of clinical benefit be carried out after approval, as needed.

To look at pyridostigmine bromide, FDA is considering DoD's proposal to base approval of pyridostigmine bromide on surrogate animal challenge studies. Currently, DoD has submitted data showing blood cholinesterase inhibition by pyridostigmine bromide and proposed that these data, based on studies of protection against nerve agents by pyridostigmine bromide in animals, be used as a possible surrogate endpoint of effectiveness.

Because clinical data from controlled trials cannot usually be obtained to support the effectiveness of antidotes or prophylactic agents, like pyridostigmine bromide, the more likely means for collecting additional data would be encounters with toxins or toxic agents in warfare situations or accidental exposure where data collection and interpretation from such non-randomized experiences is often difficult, at best.

Turning to botulinum toxoid vaccine, one of the difficult scientific issues is that classical clinical efficacy trials may not be feasible for some vaccines, including botulinum

toxoid vaccine. For example, there is no appropriate population to access for entry into a randomized, well-controlled efficacy trial for botulism. In the general population, botulism is an outbreak disease of very low incidence.

Also, challenge studies of normal

vaccinated volunteers would not be acceptable in this instance because botulism can be a lethal disease for which there is no specific highlyeffective treatment. It is clear that there are major ethical issues for deliberately exposing any group to such toxins, with or without protection.

To overcome the problem with botulinum

toxoid, FDA has an ongoing dialogue with the military to address these issues, as you have heard. The military is attempting to construct a scientifically-based argument that toxinneutralizing antibody is a reasonable surrogate for vaccine efficacy, based on human serology, toxin neutralization data, and animal challenge protection data. This type of toxin neutralization is very well understood from an immunologic standpoint for other licensed bacterial toxoids.

Of relevance in this regard is a statement

from the December 13, 1985, FDA Federal Register notice, page 51,005, which pertained to the implementation of efficacy review for bacterial vaccines and toxoids licensed prior to July 1, 1972. It says, "In diseases like diphtheria, tetanus, and botulism, neutralization of the soluble bacterial toxins, or exotoxins, liberated during infection is of the utmost importance in the prevention of the diseases caused by the organisms. Thus, antibodies that neutralize such toxins are the basis of antitoxin immunity, which constitutes an area of immunologic knowledge that is on a much firmer basis than the understanding of many forms of antibacterial immunity."

Non-human primates and some small animals are good models for botulism. Available animal data provides some support for the efficacy of this vaccine, both by the intraperitoneal and aerosol challenge route. The Army has estimated that rigorous animal studies for each type in the vaccine, A, B, C, D, and E, would cost in excess of $1 million in total, but it is willing to undertake them.

It is also noted that no cases of botulism have been reported under the investigational new drug application used in over 3,000 vaccinated lab workers at risk. However, the lab worker data, including documenting protection from accidental exposure, by itself, would not be sufficient proof of efficacy to support licensure.

I would now like to comment on some

ethical issues. As discussed previously, it is not ethically acceptable to conduct efficacy studies for prophylaxis or treatment for chemical and biologic warfare agents or antidotes to severelytoxic agents. This, however, does not necessarily preclude products from being approved, based on surrogate markers of effectiveness.

It should be noted that a number of other countries, including our NATO partners, have fielded pyridostigmine bromide for many years as part of their armamentarium for counteracting

chemical warfare agents. I think it is noteworthy to say this in light of what we had heard in the testimony previously about the very close working relationship that we do have with NATO countries and others. So other countries are currently doing things with these products in terms of fielding them in a way similar to what had been done by us.

In terms of our interaction with the

Department of Defense, FDA has a longstanding history of working closely with the Department of Defense on their development of investigational agents. This relationship is articulated and facilitated by a memorandum of understanding between FDA and DoD that dates back to 1974 and was most recently reissued in 1987.

As noted above, FDA has an ongoing dialogue with the military on the licensure of botulinum toxoid vaccine. Recently, DoD provided FDA with a plan for product manufacture, as well as preliminary clinical and animal data to support licensure, and a meeting occurred in mid-April on the topic.

There has been ongoing dialogue concerning the use of surrogate endpoint model of cholinesterase inhibition and certain data that DoD had submitted for FDA review in possible support of a new drug application, an NDA for pyridostigmine bromide. And again, you just heard about the most recent situation with that. FDA and DoD meet as necessary on this particular topic.

Before concluding, I would like to make several observations. Regardless of the approval process, there may still be a need to be able to use an investigational product should a military situation occur at a time when the best available prophylaxis or treatment is still in an investigational status. We, DoD, and society in general would be happier if we did not need to use investigational products, but it does seem that we must continue to have the option available should a military occasion arise where the best medical approach is the use of an investigational product.

As stated above, we look forward to

obtaining your comments and those of the general public on our informed consent waiver proposal and on this topic, as well.

At this point, Dr. Temple, who has

arrived, and Dr. Goldenthal and I will be happy to respond to any questions that you might have.

CHAIR LASHOF: Thank you very much, sir. One question I have is you mentioned the

ongoing work with the other countries, as did the previous speakers. Is FDA able to use data and information gained from other countries if that is submitted as part of the approval process from DoD? Can you use that, or do we have to have our own?

DR. NIGHTINGALE: I am going to ask Dr.

Temple to say something about that after I make a preliminary comment, and that is, we have tried ourselves to make contact with our colleagues in other countries. In some cases, we have been successful in making contact. I would say it is a topic that is not one readily talked about by our regulatory colleagues in other countries.

In fact, I think that in one case that I know of, we were able to get some information.

Whether or not that can be used again, Dr. Temple will talk about that.

But there is a problem in this area where I think the military has a much better ability to get information and provide information to us on what is happening in those countries and we certainly have been attempting to work with the military on these issues.

Bob, would you like to say something about specifics and use of data?

DR. TEMPLE: Are you asking specifically whether we could use data that were collected in a foreign circumstance? Sure. That's not a problem. We haven't been able to come up with anything yet that we didn't already have access to, and I think DoD has tried to do so. There were rumors early on that someone had actually done a human trial, but we've never been able to establish that or find it or--

CHAIR LASHOF: I thought there was a policy in FDA, I mean, a drug that's approved and licensed in another country has to still go through certain procedures in this country. So the real question was, how much of the data that was presented in the other country that got it an approval can be then used in this country in the process? You're saying that you can use that data?

DR. TEMPLE: Yes, all of it can be. It

still has to go through an approval process, but there's no impediment to using data from foreign sources.

DR. NIGHTINGALE: I think that really the issue is one of getting the information. I don't know how successful Bob has been, but I really know of only one country where we have been able to get to the specifics of a particular product, and yet it is the NATO countries are all fielding pyridostigmine bromide, for example, and we know that there has been a fair amount of use and countries are able to do this.

We do know that we pretty much stand alone, I think, in having to be concerned about informed consent and the waiver problem in our country, which, again, suggests that the other counties have, in some way, been able to approve the very same product that we are considering to be investigational.

CHAIR LASHOF: In other words, you are saying the pyridostigmine bromide is actually approved as an approved drug, not as an investigational, for use as an antidote, treatment, prophylactic measure?

DR. TEMPLE: I don't think we know enough about the exact circumstances of distribution in all those countries, whether they have special arrangements for their DoD-equivalents or things like that. Pyridostigmine, of course, is available in all countries as a drug.

CHAIR LASHOF: Well, it is available for other treatment, yes.

DR. TEMPLE: But I couldn't say that they've approved it, using their ordinary process and the usual rules for approving therapeutics, or whether they have special arrangements or what. But in the end, whatever they're doing, they're relying on approximately the same data we have

access to. They may have a system that permits more ready reliance on animal data when there aren't human data, but I don't think we really know the exact circumstances and legalities of how they make it available.

CHAIR LASHOF: Then I suspect the answer

to the next question is no, but I'll ask it anyway. Are we able to get information from them on any interaction between pyridostigmine bromide and other drugs in their field use?

DR. NIGHTINGALE: I don't think we've gotten to that stage yet, but clearly, if we can unlock the--

CHAIR LASHOF: That will be the next question.

DR. NIGHTINGALE: Clearly, though, we would want to get all the information that we could, and there are--I mean, in this country, DoD wants to follow, indeed, has this MOU with us that requires that they work with us and use the IND process and get informed consent. I think in some other countries, for example, if their troops are able to purchase a drug in another country, they may not be so concerned about the mechanism of approval in their own country. I know this happens in some cases. But that's not the way it's occurring here and I think DoD and the FDA are doing the appropriate thing.

CHAIR LASHOF: In looking at the question of approving pyridostigmine, as you look at the new application and work with DoD around it, will you be trying to address or get DoD to address the issue of the use of pyridostigmine bromide under conditions in which the people are exposed to other agents, such as pesticides?

DR. TEMPLE: I am not up to the minute on the review, but certainly, especially given some of the most recent data, we would certainly be asking questions about what are generically called drugdrug interactions. We are always interested in that. How much data we will have access to or there will be, I don't know, but--

CHAIR LASHOF: At this point, I think we've heard that DoD isn't looking at that question, is not addressing it. If you are going to look for it, it might be wise to let them know that you want that information.

DR. TEMPLE: Yes. Apart from some of the very early insect studies, the ones in higher animals are relatively new and I'm not sure we've come to grips with it yet, but I don't think that kind of question can be ignored.

MS. TAYLOR: You might have answered this question, but in other countries, pyridostigmine bromide is being used as a prophylactic treatment for chemical warfare currently, right?

DR. NIGHTINGALE: Right. It's a

pretreatment, used the same way--

DR. TEMPLE: Much the same way that we did.

MS. TAYLOR: So we're using it in the very same application, or do we know?

DR. TEMPLE: As far as we know. I

couldn't say that the rules under which you use it are identical or anything like that, but the idea is the same, that when there is a perceived threat

of exposure to nerve agents, it would be deployed. DR. NIGHTINGALE: And I think it is the

same dosage.

DR. TEMPLE: Yes, I think it's the same dose, and I know there is some history of use. To my best knowledge, no problem has been identified with it, but I don't know whether it's as extensive as the use was here or questions like that.

CHAIR LASHOF: Other questions? Elaine? MS. LARSON: Both of the agents we're

discussing had fairly widespread use in the Gulf. What, if any, information from the Gulf is usable for you? That's the first part.

The second part is, if this happens again, what kind of data should be collected so that it will be more usable and we aren't six years out from the war and still not have the data we need?

DR. NIGHTINGALE: Bob, do you want to go

first on pyridostigmine?

DR. TEMPLE: Yes. That's a good question, and one of the difficulties is that, at least as we were told, the only way to use it was you didn't have a one-to-one relationship between someone says, "Use this and I'll follow up and see what your outcome is." What was done instead were sort of survey instruments. There were several. One was actually published, about 50,000 estimated exposures in airmen, I guess.

I don't think anybody is satisfied,

including DoD--they have said they aren't--with the usefulness and diligence of those attempts. But it isn't too obvious how to do it better.

One of the things we are certainly thinking about is how to collect better information if there is another deployment, and I would say we are interested in that question generally. But there isn't a point, or at least as it was deployed, there wasn't a point at which someone says, "Take this," and therefore you have a denominator. There wasn't anything like that.

So you're guessing about denominators, and then the way people were discovered, the numerator was discovered by whether people came to the medical facility and complained. That's not so good even for epidemiology, and so you have to take all of the findings with some knowledge of what they are.

I don't know if I know how to do that better, to answer that question better. There are things you could do, of course, if you simply wanted to learn about the immediate toxicity of pyridostigmine bromide. You could, I think--I suggested this once before a Senator, so I'll suggest it again--you could, if you thought this was helpful, randomize a large number of people to taking a dose and seeing what the rate of side effects are. After all, the potential is that it's going to be deployed. That seems the sort of study one might contemplate.

Of course, the real questions, I think, now are whether there is some interaction and whether you can actually study an interaction you are quite worried about starts to get ethically dicey. But there are specific questions one could ask in a more controlled setting if they were thought to be the reasonable questions.

MS. LARSON: But in all fairness, if you all don't set the criteria, then it's a moving target and we'll never be able to answer these questions.

DR. TEMPLE: We did agree before the investigational use that there would be attempts to follow up the outcome of dispersion. I don't think we had a very clear idea of how well that was going to work, having had no experience with that setting before, and I think nobody thinks it worked all that well.

We are thinking about and will be talking with DoD about how that sort of thing might be done better, in particular because one of the ground rules for the use of the accelerated approval rule is that you have to establish the clinical benefit, somehow, of the drug. Ordinarily, one thinks of doing that in controlled trials. Well, what does a controlled trial mean in this setting?

One of the things we have to determine before we can decide that the accelerated approval rule is even usable is how the evidence of clinical benefit would be derived. So we are going to have to come to grips with how you can do the best study possible in that setting and see if we think it will work. If people have figured that out yet, they haven't told me, but we'll be working on that because it's critical for us.

MS. LARSON: What is the time line, then? You laid out the process very nicely and so forth, but what's the time line for these two agents, for example?

DR. TEMPLE: The pyridostigmine application is under review. I can't tell you what its due date is because I don't know and probably shouldn't state it publicly anyway. But as is known, we initially didn't accept it for filing because of some chemistry problems, and I know that it's under review, but I can't tell you where in the year that we have to review it it is.

DR. NIGHTINGALE: Do you want to hear about the botulinum toxoid experience?

DR. GOLDENTHAL: Basically, the botulinum toxoid vaccine, there is data available through two studies from the Gulf War experience. One was a postcard survey that suggested that the rate of the common reactions to the botulinum toxoid vaccine was similar to that seen under the CDC IND experience.

A second study, which was done or started about a year and a half after the Gulf War involved immunizing troops with the botulinum toxoid vaccine and/or the anthrax vaccine if they had received it during the Gulf War. That study had a couple of features to it. They looked at antibody titers, so you could see that if the individual's antibody response could be boosted, that would indicate that they had an immune response to the respective vaccines during the Gulf War and it was also a way of looking at potential interactions between the botulinum toxoid vaccine and the anthrax vaccine, albeit in a limited number of individuals.

With regard to how to do it better, for vaccines, I think it is very useful to record the vaccine usage, whether it is a licensed vaccine or an unlicensed vaccine, because downstream you get

into the issue of who gets boosted and at what intervals, so you really need to have that information. We have had talks with DoD about contingency protocols and we certainly have emphasized recording the use of the investigational vaccine.

We have also focused on getting some information about sort of the common local reactions in a subset of individuals and then having the mechanism for capturing any serious reaction that may happen. I don't think it's necessary to record the common local reactions on every single vaccinee. I do not think that that is necessary. But again, getting it on a subset of vaccinees, plus having a mechanism for capturing any serious reaction that may occur, I think, is a reasonable approach to take.

CHAIR LASHOF: Do I gather from that that we probably should have enough data from the Gulf War to make a determination as to whether the botulinum vaccine can be licensed rather than as an investigational?

DR. GOLDENTHAL: My view is that the CDC data base of over 3,000 vaccinees is probably the best data base, because there, there is detailed observations about both the local common reaction and also any systemic reactions that occurred, and in the CDC data base, you have people who have received many boosters and it is over a fairly long period of time, whereas with the Gulf War experience--I understood that there were about 8,000 individuals who were immunized with the botulinum toxoid vaccine. The studies to date, I believe, only have maybe a couple hundred individuals total. So really, the CDC data base of over 3,000 individuals is the most valuable data base for giving clinical safety and immunogenicity data to support licensure.

But there are additional data that will be necessary. We would like to see additional immunogenicity data with all of the serotypes because most of the information in the IND is with three of the serotypes, so we want to make sure that we've got all of the detailed immunogenicity data in humans on all of the serotypes, although certainly, the available data in the literature certainly suggests that the vaccine is immunogenic.

We would also like to see, since we're

talking about what would be needed for licensure in terms of data, in addition, some additional human immunogenicity data, which can be readily obtained. The military is going to provide some additional challenge protection data in both small animals and non-human primates for all five serotypes and also looking at the aerosolized route of challenge in some detail, getting a good sort of dose effect and some detail information about protection.

The available challenge protection data look quite promising, both by the intraperitoneal route and the aerosolized route, but again, the military is going to get some more detailed, definitive data that will hopefully allow us to license the vaccine.

CHAIR LASHOF: Do you have a time table for when you think you might be able to make the decision about the licensure of the vaccine?

DR. GOLDENTHAL: The DoD is going to be providing us with some additional animal and human immunogenicity data. I am not certain of what their exact time table will be, but maybe someone from DoD would like to comment on that.


MS. LARSON: Dr. Nightingale told us that it was $1 million for the animal studies.

DR. GOLDENTHAL: That was DoD's estimate. MS. LARSON: In addition, the

immunogenicity studies for humans is not included in that number. What is the sample size for that that you need?

DR. GOLDENTHAL: Probably, it won't be that great because maybe you would have--this is just an estimate, but maybe you would have 50 to 100 per type. You would look at the immunogenicity to the five types.

MS. LARSON: If they are going to do the studies, they've got a minimum number they need to do. They don't just have just an estimate of 50 to 100, right? Who tells them how many they have to do?

DR. GOLDENTHAL: They will submit a protocol to us with specific statistical justification for their sample size.


DR. NISHIMI: Dr. Temple, FDA's testimony states that, in several cases, that efficacy studies for CBW antidotes and pretreatments in humans by exposing them specifically to the agents just aren't feasible. Would you concur with that?

DR. TEMPLE: It certainly is true that

most people who have examined this question have concluded that these studies are not feasible. I'm not 100 percent sure that, if pressed, one couldn't think of a way to do them, but it's an extremely delicate matter and it's obviously a very delicate matter for the Department of Defense to even contemplate this.

It doesn't seem inconceivable to me, but I think people who know nerve agents better than I do would have to weigh in on this, that very low doses, gradually approached, in incredibly wellinformed volunteers, might not be possible to study. But I have to tell you, no one I have ever suggested that to has ever agreed with me, so you should know that.

But the consequences of these agents are not completely mysterious. There are ways of controlling for respiratory depression and things like that. So I'm not 100 percent sure, but I think you wouldn't do that or even think about it if you were reasonably persuaded that you understood from the human cholinesterase data and the animal data that you were pretty sure it was going to work.

But if there were major doubts about that and if this is important, which, heaven knows, it is, I'm not sure that something like that couldn't be contemplated. But let me say I'm speaking personally. This is absolutely not FDA policy, and as I said, everyone I have ever suggested that to has disagreed with me.

DR. NISHIMI: Thank you.


DR. PORTER: I have a question for Dr. Nightingale. Exactly what process is FDA going to use to decide if it will approve drugs and license vaccines that are pretreatments and prophylaxis for chemical and biological warfare agents? How are you progressing in coming to your conclusions on that?

DR. NIGHTINGALE: I guess the first thing to say is this has certainly reached the attention of the senior management of the agency. Everyone is very interested in doing the correct thing. It's clear that it's a public health, it's a U.S. Government priority to see that, if approval is possible, that it occurs. Obviously, the statutory requirements have to be met.

So what we are doing is we are, as there is the interaction at the scientific and technical level on the various applications, there is a senior group within the agency meeting to discuss mechanisms. I don't think anyone is going to tell someone, well, you must approve it under accelerated approval or standard approval. That's not really the issue.

The issue is how to move ahead with the data at hand or the data that come in. We need to, if possible, take action. So it is something which is being monitored and coordinated at the senior agency level.

There are policies involved, of course, in this. If one uses a particular mechanism for approval, what does this mean? Does it set a precedent of a certain type? What are the legal and scientific issues? So it is recognized as a complex, difficult, but urgent matter. The fact that this Committee has taken a real interest, I think, is salutary in terms of our moving ahead, just as you have helped us also on the informed consent waiver approach.

DR. PORTER: Do you propose to have groups outside of the agency weigh into this decision?

DR. NIGHTINGALE: I would say that has not

been decided at this point. It is certainly something that we will be discussing.

DR. TEMPLE: We clearly have not rejected the concept out of hand, which means we think it's worth considering, and will do that. To some extent, the details of what is known will determine the outcome, how persuasive the animal data are, how good a surrogate it is.

As I said before, I think a very important part of this is, can we honestly say that the clinical data would be available, which is what's required under this rule? If you can't, then I think it becomes a dicey question as to whether you can do this in compliance with current law. But I don't think we've considered that fully and we certainly haven't thrown our imagination fully into seeing how assessment of exposure could be made and things like that. So I think it's novel for us.

As I've told some of your group before, we

face this every time it's uncomfortable or impossible to administer the toxic substance. We have had other situations in which that was difficult, too. So we are interested in thinking about the problem in the general way, too. It isn't only the Defense Department.

DR. GOLDENTHAL: Actually, our plan is to take the botulinum toxoid vaccine to our vaccines advisory committee after the military reaches a certain milestone on their animal testing, which I think will occur in 1996, just to show the advisory committee the entire issue and get their input on it.

I might add that that quote that Stuart read earlier about diphtheria, tetanus, and botulism neutralization being well understood, that was actually a quote from a vaccines advisory committee that was published in the Federal Register in 1985. So I think that they will have to see what the data looks like and the particulars, but I think it's a reasonable approach.

CHAIR LASHOF: Let me follow up on that, too. I may be missing something here, but it seemed to me demonstrating neutralizing antibodies is as good evidence as you would want. I just wonder why you need to spend $1 million for animal studies if we have vaccinated some 8,000 troops that we could get additional serum from and test them for neutralizing antibodies, why that isn't a reasonable enough surrogate to go ahead on botulinum.

DR. GOLDENTHAL: I guess the scientific view in the agency is that the challenge--some detailed challenge studies in animals, which really gives you a better idea, a little more insight into the titer and what troops can be protected from in an aerosolized situation, would be very valuable and help us with more specifics of the labeling.

Certainly, the neutralizing antibody in

its own right is very good, but again, I think it requires a combination of the animal challenge studies and the neutralization. But I would agree that the neutralizing data on their own are fairly strong. I am hoping that when we get the whole package, if the data look good, that we will be able to give this a regular approval, in fact, rather than an accelerated approval, but I won't know until I see the whole data package.

CHAIR LASHOF: Thank you. Other


MS. TAYLOR: I just have one, going back to the pyridostigmine bromide tablets. In examining the safety of the drug for its use, has that been done among humans or animal models to determine how safe it is?

DR. TEMPLE: There was a fair amount of very short-term exposure of soldiers and those data were looked at and were largely benign. But there's no question, we were influenced by the many, many year, many decade, use of pyridostigmine, at approximately ten times the dose that was going to be marketed, in humans, humans of both genders. That affected us.

Pyridostigmine and closely related drugs are very well studied in animals and have been around for a very long time. So we thought that the risk of approximately one-tenth of the dose was very low.

That was the basis for our conclusion, that the safety had been established. There was an additional acute exposures of soldiers that was

also benign, but that's how we reached our conclusion.

MS. TAYLOR: These were based on previous studies that had been conducted, or just--

DR. TEMPLE: The drug has been marked for many years for myasthenia gravis at very large doses and for very long periods of time because you have the disease until someone takes the tumor that caused it out or whatever, but you have it for a very long time. So we thought there was a very large experience, again, at an order of magnitude greater dose and that that was very reassuring. Then there was nothing in the DoD studies that suggested any grounds for further concern.

We had not, I can tell you, thought about the interaction potential that has emerged, so-

CHAIR LASHOF: Has anybody looked to see

whether there are any pesticide applicators who have myasthenia gravis or are on pyridostigmine bromide? Can we go searching for some?

DR. TEMPLE: I doubt it. Most of them have thymic tumors, I think, but--

CHAIR LASHOF: Are there other questions? If not, with that note, we will thank you very much for your help and your testimony here today.


bit of work.

DR. NISHIMI: At this point, it would be useful for the Committee to provide some feedback to Committee staff on whether they felt they needed some additional information on the matters that we have discussed, outside of the ones that you have mentioned in the course of questioning on the CBW issue, and then I could go through what we intend to cover in the next couple of meetings and that schedule.

If there is anything that has come to mind overnight or during the day that wasn't mentioned, it would be useful for us to know now so we can begin getting that information for you. That would be CBW-specific information.

MS. LARSON: The only question I have is, have we covered fully pyridostigmine? I'm just asking the rest of the panel members.

CHAIR LASHOF: Have we covered the issues around pyridostigmine bromide adequately--

MS. LARSON: Right, because this is-CHAIR LASHOF: --or is there further

information people would like on the pyridostigmine bromide?

MS. TAYLOR: I would like some more

information. I am still not clear whether this drug is actually safe in all of its uses, particularly if you are talking about some other effects with combinations of pesticides or other drug use.

CHAIR LASHOF: We do know that the studies at Duke are to be published in the Journal of Toxicology. Hopefully, we obviously are planning to get that article. We will review it thoroughly. Then I guess we could consider whether we would like the investigators who did that work to appear and whether we would like others who may be knowledgeable in that area who are trying to look at it also to appear and have some panel discussion

around that issue, or staff to brief us on what they have learned. They have met with the investigators, I believe, at one point, and may have more data.

DR. NISHIMI: What I should note is that-what I would have said in about probably five minutes is that the July 8 and 9 meeting in Chicago will be devoted specifically to health effects, and so we would have been certain at that meeting to incorporate what we knew at that point about the relationship of PB to other possible chemicals, as well as explore the issue of health effects of depleted uranium, infectious diseases, the many risk factors that were listed in the President's mandate.

MS. LARSON: July 8 and 9?

DR. NISHIMI: That is right, July 8 and 9 in Chicago.

CHAIR LASHOF: Let me ask about that one. Well, let's wait.


CHAIR LASHOF: Let's see whether there is anything around the CBW issue other than pyridostigmine bromide that has come up that you would like to know more about. John?

MR. BALDESCHWIELER: The only new thing I am aware of is the interaction issue.

CHAIR LASHOF: Yes, with the pesticides, right, and that we will deal with in the July meeting in Chicago. Are there any other issues that have come up yesterday and today that you need further information on?

If not, let's move to what are the issues you will be covering in the July 8 and 9 meeting, at this point that you have on the agenda for that, and see whether people want other things that you haven't got on your agenda yet.

DR. NISHIMI: We do not have invited speakers on the agenda. We anticipate that we will have a great deal of staff work involved in looking at the risk factors, and again, there are, I think, seven of them listed specifically in the charter and there are others not specifically mentioned that the staff has been doing research on.

We would report to you back on the staff's research, as well as filling that out, if necessary, with additional speakers. Then we would be looking for the Committee's input then on the various risk factors. I do anticipate that that will take up the majority of the meeting, because there are many risk factors that the Committee will need to evaluate.

MS. LARSON: I would like to see reports from the staff on the site visits.

DR. NISHIMI: The clinical care and

clinical access issue? The site visits, I anticipate, would be covered in the September full Committee meeting, yes.

CHAIR LASHOF: Others? Maybe it would help, then, if you would run through the meeting schedule and what you are planning to highlight.

DR. NISHIMI: In June right now, there is

no scheduled date. It is not clear to me if we will have a panel meeting in June. That possibility remains open.

In July, on the 8th and 9th, we do have

space approved and secured in Chicago, as I indicated.

On July 23, we pushed DoD and they approved it today, so I can announce it, there will be a panel meeting in Cincinnati focusing on some of the issues surrounding stress, and Dr. Cassells and an assistant have been working on that issue. Dr. Hamburg will chair that and will be in touch with you as to your availability and/or interest in that. That will be a panel meeting.

Then there may be an additional panel meeting between then and the next full Committee meeting in September, depending on Dr. Lashof's and the Committee's feeling on whether or not we need another specialized meeting or whether we can just move to full Committee meetings in September, October, and November, in preparation for delivery of the final report to the three Secretaries before the end of the year.

Those meetings, we are in the process of getting approval to use non-government space and to secure the contract, and I hope to get back to you at least with some tentative ideas in about a week or two. It will take longer to actually formalize those arrangements, obviously.

MR. BALDESCHWIELER: What about the dates? DR. NISHIMI: That's what I was just

saying. I hope to be able to get to you in a week or two on holding possible dates, but I would not be able to finalize those arrangements. But I hope to give you some idea of a two- or three- or fourday window in a couple of weeks.

CHAIR LASHOF: As it stands, the September, October, and November would really be not planned for outside testimony except as we work through anything else that comes up, but would be primarily for the Committee to come to grips with our final report?

DR. NISHIMI: I could see there being a reasonable amount of invited testimony to, perhaps, the first and even first day and a half, let's say, of the September meeting. I think there may be issues at the July meeting that surface and I'm comfortable with the staff's ability to put together that kind of meeting and be fully prepared, as we were for San Diego, to then proceed with that kind of a discussion, report language, and then review of the report in October and November. I think we can handle that both by meetings and mail, as we did for the interim report. So September would perhaps be a hybrid of the two, speakers and staff work.

CHAIR LASHOF: Are there any Committee reactions to that kind of a time table? We regret that we can't give you hard dates, but it's the process of getting approval for the buildings and so on.

MS. LARSON: The sooner, the better. CHAIR LASHOF: We do have tentative dates

of when people looked like they were available, and those are the dates you're working around.

DR. NISHIMI: Those were the working dates that we had, and obviously, we know that the situation has changed, but it seems like that's the best we're going to get regardless, I think.

CHAIR LASHOF: If you have that original

list, look at it and try to keep as many dates open as you can and we will get to you as fast as we can.

The September one, you will be covering the site visits, the clinical site visits.

DR. NISHIMI: Yes, yes.

CHAIR LASHOF: Then all the others, staff have been doing a tremendous amount of a number of issues.

DR. NISHIMI: Right. We would start wrapping things up.

CHAIR LASHOF: You would start wrapping those up and getting us that kind of information. It sounds good to me. Does anybody else have any burning issue, anything you would like to pursue?

MAJOR KNOX: I had talked with Holly at

lunch about still the veterans compensation and she mentioned to me that they were looking at a sample size from the White House of people who had been denied. Something like 400 had been denied. I think we need to follow up on that, particularly those that have been denied because they were not ill within the two-year period.

DR. NISHIMI: What Marguerite is referring to are twofold. Tom McDaniels and Holly Gwyn received a briefing from the Veterans Benefits Administration on compensation issues, and at that briefing, they indicated that they were relooking at a subsample of individuals who had been denied compensation in order to reevaluate the basis for that denial.

In a separate instance, Secretary Brown recently testified before one of the Congressional Veterans Affairs Committees, I believe the Senate side, that he had instructed VA to again relook at the denial claim rate for Gulf War veterans, and so I would anticipate that that would be the kind of information that we would discuss again in that September meeting when we are trying to wrap up all the various elements of the Committee's charge.

CHAIR LASHOF: I think on the compensation

issue, that one of the things that I don't understand at all, and I assume staff will have figured it out by then, being as brilliant as they are--

DR. NISHIMI: No doubt.

CHAIR LASHOF: --if we don't know that there is any illness caused by service in the Gulf, how the VA decides who to compensate and who not to. You are going to find that out for us?

DR. NISHIMI: The charge specifically mandates that we look at compensation and coordination, not compensation of cases per se. And yes, compensation cases will be--

CHAIR LASHOF: But policy, what is their ongoing policy?

DR. NISHIMI: Correct.

MAJOR CROSS: So the answer is, yes, we will look at that?

CHAIR LASHOF: Yes, we will get a report on that.

Is there any other business that comes before us? If not, Cliff, you have the opportunity to perform your duty again.

MR. GABRIEL: I want to thank the

Committee and the staff for all their hard work,

for the speakers, the observers. I think it was a great meeting. I want to really enforce the fact that I am really looking forward to working with the agencies in trying to get information to the Committee in a timely manner.

With that, the meeting is adjourned. [Whereupon, at 3:07 p.m., the meeting was


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I, Gwen A. Schlemmer, Official Court Reporter for Miller Reporting Company, Inc., hereby certify that I recorded the foregoing proceedings; that the proceedings have been reduced to typewriting by me or under my direction, and that the foregoing transcript is a correct and accurate record of the proceedings to the best of my knowledge, ability and belief.