59

US cohorts; compare symptom prevalences in the Gulf-deployed Danish troops and those not
deployed; and test the validity of the LAD findings with the Danish subjects.
For Priority Area 2, Dr. Howard Kipen of the University of Medicine and Dentistry of

‘New Jetsey-Robert Wood Johnson Medical Schoo! will conduct a study entitled “ Defining Gulf
War Illness.” The purpose of this study is to characterize and compare alternative classifications
for symptoms and functional disability which remain medically unexplained in Gulf War
veterans. This will be accomplished in three phases. Phase I will assess persistence and stability
of symptoms over time, as well as compare the performance of data-driven case definitions
derived from two samples: 1) the New Jersey Center for Environmental Hazards Research
sample of Gulf War veterans participating in the Department of Veterans Affairs Gulf War
Registry (N= 1,161), and 2) a cohort of Air Force members from a previous CDC study of Gulf
War veterans and Gulf War-era controls from Pennsylvania and Florida (N=3,723). All subjects
from the previously studied New Jersey cohort and a sample of the CDC Air Force cohort (N=
1,400) will be administered a symptom questionnaire. In addition to assessing data-driven case
definitions for illness among Gulf War veterans, existing definitions for medically unexplained
symptoms, such as chronic fatigue syndrome, multiple chemical sensitivity, and fibromyalgia
will be evaluated. Phase I will attempt to assess the generalizability of both derived and existing
case definitions in a National random sample of deployed and non-deployed Gulf War era
veterans (N=3,000). Phase III will consist of a standardized telephone interview for the
assessment of psychiatric conditions. This will be administered to a sample (not to exceed 600)

of Phase I and Phase II participants who are identified through their responses to paper-and-


123

Mr. GERRITY. Certainly.

Mr. SANDERS. OK. Thank you.

Mr. SHays. Why didn’t you say that the first time? You have the
expertise. It would have been very helpful to us. It would have
made me feel like maybe we were wrong, that maybe there isn’t
any resistance to focusing on chemical exposure.

But there seems to be a resistance to just saying the truth: Low-
level exposure to certain chemicals can lead to chronic illness and
death, period, case closed. And because of that, we’d better study
it. And that’s what causes my frustration.

I didn’t come to be frustrated. I can’t get an answer that frus-
trates me.

Do you want to say something, Dr. Feussner?

Dr. FEUSSNER. Yes, sir. I was just going to followup to say that
until recently, our Department did not have a focused research ef-
fort dealing with environmental hazards, and that research focus
really wasn’t created until 1993-1994, with the funding of environ-
mental hazard centers in Boston, Portland, East Orange and most
recently a fourth focusing on birth defects and exposures that
might cause birth defects.

e second issue, I would say, is that with the creation of those
environmental hazards, we also started funding research, looking
at multiple chemical sensitivity as a condition, using working case
definitions, since a more definite case definition for that problem
is also somewhat illusive. And we have projects nested primarily
within our environmental hazards program in Boston, and East Or-
ange, NJ, but have also funded a project that came through the
VA’s intramural program, not part of the Persian Gulf research ef-
fort, in Tucson, dealing with chemical intolerance.

So I think that we have not had an extensive research capacity
in this area in the past. We have worked since 1993 to try to rec-
tify that. We have funded centers of excellence, environmental haz-
ard centers, in trying to address those issues.

Mr. SHays. The challenge is, though, we still have a handful of
doctors who have expertise within, and there are people outside.

Let me just ask two other questions quickly and they don’t need
long answers.

xcuse me. I will go to Mr. Allen and then we will come back.

Mr. ALLEN. Thank you.

Mr. SuHays. Mr. Allen, you have the floor.

Mr. ALLEN. Thank you, Mr. Chairman. I will, I think, follow
along in this vein.

As I listen to this discussion, a couple of things come to my mind.
I had some background years ago representing some plaintiffs who
were affected by an aerial spraying incident. A paper company up
in Maine sprayed an herbicide in an area where it drifted and it
affected their gardens. So this long story—I just say that by way
of background; this is an area where I have some little amount of
knowledge, and a little knowledge may be a dangerous thing. But
it does seem to me that one of the things we have to get in line
is what our expectations are for an outcome.

I do not expect that there is a cause to a Gulf war illness and
that you--and that, at the end of the day, whether that is 5 years
or 10 years or 20 years, there will be research which shows that,


25

biologicals, preventive medicine guidance, standards, diagnostics, treatments, and devices that are
provided to medical and non-medical users in various operational communities.

The ASD(HA) uses and applies results from this program to support doctrine development,
force structure, training, and military operational considerations. The Defense biomedical RDA
program is different from the ASD(HA) health care programs. Thus, the ASBREM Committee
provides DoD with the capability for effective technology developer and health care provider
interactions. This is important for resolving GWVI-related issues and other research and health
care matters.

Purpose of GWVI Research Program

On August 2, 1990, Iraq invaded Kuwait. Within five days, the United States began to
deploy troops to the Persian Gulf in Operation Desert Shield. In January, 1991, United Nations
coalition forces began intense air attacks against the Iraqi forces (Operation Desert Storm). On
February 24, a ground attack was launched, and within four days, Iraqi resistance crumbled.
Almost 700,000 U.S. troops participated in the Gulf War. Most troops retumed home and
resumed their normal activities. However, a number of those who had been deployed to the
Persian Gulf began to report health problems they believed to be connected to their deployment.
These problems included symptoms of fatigue, headache, memory loss, depression, anxiety, mood
changes, sleep disturbances, muscle and joint pain, and persistent rashes.

I want to emphasize that the Department is committed to an aggressive, coordinated, well-
focused but broadly scoped and strong GWVI research program that does the following:

‘* furthers the fundamental understan

© provides enhanced diagnostic capat
veterans; and

‘supports the establishment of policies and preventive measures that minimize the risk of
such illnesses during future military operations.

of the illnesses;
ities and efficacious treatment modalities for

We also are committed to ensuring that our research program is of the highest quality. We
‘use competition and independent peer review to secure the very best research performers,
hypotheses, and experimental designs, from all possible sources, including the Federal, civilian,
national and international communities. This commitment follows an appreciation at all levels
within the Department of our responsibility to achieve an optimal investment of taxpayer dollars,
to assist our Gulf War veterans secure diagnoses and treatments for their disabilities and illnesses,
and to prevent such disabilities and illnesses as a consequence of future deployments.

Federal Interagency Participation in GWVI Research Program
As you are aware, our research program and findings on GWVI are coordinated and

integrated with those of the Departments of Veterans Affairs (VA) and Health and Human
Services (HHS) through the Research Working Group (RWG) of the Persian Gulf Veterans’


154

a study's precision or statistical power is also linked to the
extent of the exposure and the accuracy of its measurement.
Inaccurate assessment of exposure can obscure the existence of such
a trend and thus make it less likely that a true risk will be
identified.*! Similarly, if an exposure had an effect only on a

particular birth defect for example, this effect might be missed by

studying all birth defects as a group.

Although Gulf War veterans' health problems began surfacing in the
early 1990s, the vast majority of research was not initiated until
1994 or later. And much of that research responded to legislative
requirements or external reviewers’ recommendations. As noted by
external reviewers, since federal research goals and objectives

were not identified until 1995, after most research activities had
been initiated, the research reflects a rationalization of ongoing

activity rather than a research management strategy.

The government's 3-year delay complicated the researchers' tasks
and limited the amount of completed research available. Of the 91

studies receiving federal funding, over 70 had not been completed

Veterans and Agent Orange: Update 1996 (Washington, D.C.:
Institute of Medicine, 1996), pp. 99-100.

6


149

Mr. Chairman and Members of the Subcommittee:

I am pleased to be here today to discuss our evaluation of the
federal strategy to research Gulf War illnesses. We reported our
findings on this strategy in June 1997 as part of our response to a
congressional mandate regarding the government's clinical care and
medical research programs relating to illnesses suffered by Gulf
War veterans.‘ 1 will first summarize our findings and provide
some background information on the government's research program

before giving you the details on our findings.

RESULTS IN BRIEF

In short, we found that

(1) the government was not proactive in researching Gulf war

illnesses;

(2) the government's early research emphasized stress as a cause
for Gulf War veterans’ illnesses and gave other hypotheses,

such as multiple chemical sensitivity, little attention;

‘Gulf War Illnesses: Improved Monitoring of Clinical Progress_and
Reexamination of Research Emphasis Are Needed (GAO/NSIAD-97-163,
June 23, 1997).


COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT
DAN BURTON, Indiana, Chairman

BENJAMIN A. GILMAN, New York HENRY A. WAXMAN, California

J. DENNIS HASTERT, Iilinois TOM LANTOS, California

CONSTANCE A. MORELLA, Maryland ROBERT E. WISE, JR,, West Virginia

CHRISTOPHER SHAYS, Connecticut MAJOR R. OWENS, New York

STEVEN SCHIFF, New Mexico EDOLPHUS TOWNS, New York

CHRISTOPHER COX, California PAUL E. KANJORSKI, Pennsylvania

ILEANA ROS-LEHTINEN, Florida GARY A. CONDIT, California

JOHN M. McHUGH, New York CAROLYN B. MALONEY, New York

STEPHEN HORN, California THOMAS M. BARRETT, Wisconsin

JOHN L. MICA, Florida ELEANOR HOLMES NORTON, Washington,

THOMAS M. DAVIS, Virginia Dc

DAVID M. MCINTOSH, Indiana CHAKA FATTAK, Pennsylvania

MARK E. SOUDER, Indiana ELIJAH E. CUMMINGS, Maryland

JOE SCARBOROUGH, Florida DENNIS J. KUCINICH, Ohio

JOHN B. SHADEGG, Arizona ROD R. BLAGOJEVICH, Illinois

STEVEN C. LATOURETTE, Ohio DANNY K. DAVIS, Illinois

MARSHALL “MARK” SANFORD, South JOHN F. TIERNEY, Massachusetts
Carolina JIM TURNER, Texas

JOHN E. SUNUNU, New Hampshire THOMAS H. ALLEN, Maine

PETE SESSIONS, Texas HAROLD E. FORD, Jk., Tennessee

MICHAEL PAPPAS, New Jersey —

VINCE SNOWBARGER, Kansas BERNARD SANDERS, Vermont

BOB BARR, Georgia (Independent)

DAN MILLER, Florida
KEVIN BINGER, Staff Director
DANIEL R. MOLL, Deputy Staff Director
WILLIAM MOSCHELLA, Deputy Counsel and Parliamentarian
Jupit McCoy, Chief Clerk
PHIL SCHILIRO, Minority Staff Director

SUBCOMMITTEE ON HUMAN RESOURCES
CHRISTOPHER SHAYS, Connecticut, Chairman

VINCE SNOWBARGER, Kansas EDOLPHUS TOWNS, New York
BENJAMIN A. GILMAN, New York THOMAS H. ALLEN, Maine
DAVID M. MCINTOSH, Indiana TOM LANTOS, California
MARK E. SOUDER, Indiana BERNARD SANDERS, Vermont (Ind.)
MICHAEL PAPPAS, New Jersey THOMAS M. BARRETT, Wisconsin
STEVEN SCHIFF, New Mexico DENNIS J. KUCINICH, Ohio

Ex OFFICIO
DAN BURTON, Indiana HENRY A. WAXMAN, California

LAWRENCE J. HALLORAN, Staff Director and Counsel
RoBERT A. NEWMAN, Professional Staff Member
R. JARED CARPENTER, Clerk
CHERRI BRANSON, Minority Counsel

aD


119

Mr. Suays. Let me tell you the intention of the Chair here. Mr.
Towns has to go somewhere. I would like to call on him. I am going
to take 10 minutes, as well, and then we are going to take 10 min-
utes with you, Mr. Allen, if that’s all right. And then we are going
to come back.

b Mr. Sanders, if you are going to be around, we are going to come
ack,

Mr. SANDERS. I am sorry, Mr. Chairman.

Mr. SHays. No apology is necessary.

Mr. Towns.

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

After listening to the questions and the comments made, I have
a question. Based on—and it came out of that. Based on your re-
search efforts to date, what you have done up to this point, are you
in a position to recommend that we do something different if this
situation presents itself again?

Dr. FEUSSNER. Yes. I think that information obtained in a base
state—and what I mean by that is information that would be ob-
tainable before one would be exposed to the consequences of war—
would help clarify subsequent research issues as illness develops
after other conflicts. So, yes, I think that the situation can be im-
proved.

Some of our research is also focusing on trying to identify mark-
ers, sometimes somewhat retrospective markers. For example, with
exposure to chemical weapons—some of the investigators in the
Netherlands are investigating biomarkers whereby the binding of
the chemicals to one enzyme is different and longer than it is to
another enzyme. So if we could study people in a short period of
time, days, we might be able to detect exposures.

We are doing research on emerging pathogens—new infections
and new germs, trying to develop skin tests for leishmaniasis, for
example. So I think that part of the research effort is looking to
the future. The neurobiology of stress and how those hormones im-
pact on the expression of disease, the genetics of the enzymes that
are affected by chemical weapons, to be able to explain why most
of the soldiers who maybe were exposed to a chemical don’t have
illnesses but a few might, because the enzyme involved is different
in some subsets of subjects.

So I think several of those things could be done to help in the
future.

Mr. Towns. Thank you very much, Mr. Chairman. I yield back.
Thank you for allowing me the additional time.

Mr. Says. Any time.

We had 11 hearings on Gulf war illnesses, and we know it is—
we believe it is not one silver bullet; we think it is a combination
of many things.

But during the course of our hearings, there were parts that
were very distressing. One was that we felt the VA and DOD were
not listening to our veterans. That’s a documented fact. They had
incredible stories, and they weren’t being listened to. So that’s one
reason we began every hearing with the VA—with the veterans
speaking and encouraging Government officials to come to the
hearing and listen before they have testified.


68

required by Presidential Decision Directive 39 to support the Department of Health and
Human Services in making available DoD stockpiles of unique medical products in the
event of a domestic terrorism use of chemical or biological weapons. The medical
response to such an event — whether against military or civilian targets — may include
the treatment use of products not approved by the FDA for general commercial
marketing. The ability to use these “investigational new drugs” in this context may be
critical to saving lives, perhaps many, many lives. In a large emergency response
operation, as in a large military combat operation, compliance with all of the normal
FDA rules for INDs -- rules designed primarily for clinical research trials — may be
quite infeasible. If the best treatment available to save lives is an IND product, use
should not be hindered by non-feasible regulatory compliance requirements. The
responsible Federal agencies should be guided by the prime objective of allowing
medical personnel to use the best prophylactic and therapeutic products available to
protect military members against chemical and biological weapons and other
operational medical threats and to protect disaster response personnel and the public in
the event of domestic terrorism use of chemical and biological weapons.

3. The ability to" our own" requires a range of viable
President and other senior officials to consider in a military or civilian emergency,
including the option of determining that informed consent and other normal IND
requirements are infeasible.

How the responsible agencies achieve the prime objective of allowing medical
personnel to use the best products available depends on the circumstances of the
exigency presented. There needs to be a range of potentially viable options that can be
considered by the President, Secretary of Defense, Secretary of Health and Human.
Services, and other officials to meet the prime objective in military or civilian terrorism
exigencies that may arise. For particular scenarios, options might include: use of
approved products only; use of IND products under all IND rules; use of IND products
with waivers of many IND rules; and perbaps special product approvals for emergency
uses only. One of the options that should remain available is the use of an IND
product under a determination that normal IND rules, including informed consent, are
infeasible. DoD would prefer, as FDA undoubtedly would, that this option not be
used. However, we strongly believe the authority of the current rule must be
maintained as an option.

Finally, we look forward to the results of our joint FDA/DoD/OEP working
group charged to develop a range of potentially viable options for achieving the prime
objective of allowing medical personne! to use the best prophylactic and therapeutic
products available to protect military members against chemical and biological weapons
and other operational medical threats and to protect disaster response personne! and the
public in the event of domestic terrorism use of chemical and biological weapons. This
is a difficult challenge, one not likely to produce in the near term an “perfect
solution.” Therefore, we suggest the work group concentrate on developing a range of
Potentially viable options that could be considered by the President, Secretary of
Defense, Secretary of Health and Human Services, and other officials to meet the


152

Research on Persian Gulf Veterans’ Illnesses.* This agenda was
developed in response to an Institute of Medicine conclusion that
the DOD and VA should determine specific research questions that
need to be answered and design epidemiologic research to these
questions. Accordingly, most of the research sponsored under this

agenda is characterized by PGVCB as epidemiological.

The objectives of epidemiologic research are to determine the
extent of diseases and illness in the population or subpopulations,
the causes of disease and its modes of transmission, the natural
history of disease, and the basis for developing preventive
strategies or interventions.’ To conduct such research,
investigators must follow a few basic generally accepted

principles.

First, they must specify diagnostic criteria to (1) reliably
determine who has the disease or condition being studied and who
does not and (2) select appropriate controls (people who do not

have the disease or condition) .

Second, the investigators must have valid and reliable methods of
collecting data on the past exposure(s) of those in the study and
possible factors that may have caused the symptoms. The need for
2a .

(First Revision), Department of Veterans Affairs, November 199

°A. M. Lilienfeld and D. E. Lilienfeld, Foundations of Epidemioloay
(New York: Oxford University Press, 1980).

4


79

DEPARTMENT OF DEFENSE COMMENTS ON
PUBLIC CITIZEN LITIGATION GROUP'S PETITION TO REPEAL
INTERIM RULE ON THE TREATMENT USE WITHOUT INFORMED CONSENT OF
INVESTIGATIONAL NEW DRUGS IN MILITARY COMBAT EXIGENCIES

The Department of Defense respectfully submits the following
statement of reasons for urging that the petition to repeal the
interim final rule be denied.

1. When the President commits U.S. military forces to a
combat, peacekeeping, or humanitarian deployment, the U.S.
Government has a duty to take all reasonable precautions to bring
about a successful completion of the mission and a safe return of
the deployed fore

Following the terrorist bombing in June at the U.S. facility
in Dhahran, in which 19 were killed, many critical questions have
been asked of senior government officials about whether adequate
precautions had been taken to protect these military members. It
is predictable that such questions will be asked any time there
are deaths and injuries that appear in hindsight to have possibly
been preventable. This arises from the duty felt by the people
to support deployed military forces whose responsibility it is to
carry out missions ordered by the President, That support
includes an expectation that the Department of Defense and other
agencies of the U.S. Government recognize their duty to take all
reasonable precautions to promote the successful completion of
the mission and the safe return of the military members.

A vital part of that duty falls to the medical establishment
of the Government. In preparing to meet that duty, scenarios
involving hundreds or thousands of potential casualties and the
Precautions that should be taken must be considered. This
responsibility to consider threats and precautions is not
exclusive to the Department of Defense. Expertise and
authorities of other agencies are often implicated, and when they
are, these agencies share in the Government's duty to the
military forces. Any breach of that duty by DoD or any other
involved agency invites a potential calamity.


15

Both VA and DoD have undertaken new initiatives that are focused on the

neurobiology of stress and stress-related disorders. These new efforts include:

1. Part of the 1997 DoD BAA requested proposals for studies of post conflict
illnesses that extend beyond the Gulf War. These studies have been requested
to address aspects of the wartime experience that create a confluence of
cognitive, emotional, and physical factors to produce chronic, non-specific
symptoms and physiological outcomes. Proposals submitted in response to this
part of the BAA have been reviewed for scientific merit and program
relevance. The RWG made its funding recommendations to DoD and DoD
expects to announce awards of selected projects soon, Results of this research
are expected to provide new insight into the causes of stress-related disorders.

2. VA and DoD have issued a request for intramural proposals valued at $5
million for research on the neurobiology of stress. Proposals will undergo
scientific review by a joint VA/DoD appointed panel of experts, and
programmatic review by the RWG. Awards of projects by VA and DoD are
expected by July 1, 1998.

3. In June 1997 VA funded a multi-center cooperative study examining the
effectiveness of a computerized battery of neuropsychological tests that could
improve the accuracy of the diagnosis of PTSD by enabling the clinician to
rule out organic central nervous system dysfunction.

4. In July 1996 VA funded a new multi-center treatment trial investigating the

efficacy of trauma-based group therapy in the treatment of PTSD.


197

anything here. I don’t—I would really like to challenge the pro-
ponents of that to show me the evidence that stress causes any—
does stress cause brain stem dysfunction? Does stress cause subcor-
tical dementia? Does stress cause fibromyalgia? The evidence on
that is highly equivocal. There is no agreement to that. Does stress
cause peptic ulcer disease? What was the disease that was most
caused by stress that everyone would agree with? Peptic ulcer dis-
ease. Now we know that is an infection and stress probably has
nothing to do with it. Ulcerative colitis was one that was caused
by stress. Good studies show stress levels are equal in people who
will later develop ulcerative colitis. This is the emperor’s new
clothes. It is distracting us. It is taking millions of dollars to study
an idea that had no basis to begin with, still has no basis, but it
is taken for granted by the groups who are handing out the money.

Mr. Suays. Thank you. Anyone else before I ask the next ques-
tion?

Dr. Sharma, you were here last time and I remember you were
very outspoken. Do rn have any comments you want to make?

SHaRMa. Well, I think I would repeat earlier what the chair-
man said, that I strongly disagree with the method the previous
panel had proposed of studying treatments. Certainly a clinical
trial is not the way. The numbers that you are going to see are
going to be very small, they are going to be very costly, their
time—the information will not be available for a year while they
are still ill. There are some other less costly ways of studying the
effectiveness of treatment.

Mr. SHAYS. You want more research on treatment and outcomes?

Mr. SHARMA. Correct.

Mr. SHays. And you are nodding your head?

Ms. HEIVILIN. Yes.

Dr. CLauw. I would ditto the need for more research on treat-
ment and outcomes. I think that a part of that should be large clin-
ical trials because there are some fundamental issues with these
illnesses that we need to resolve as far as certain types of therapies
that we all think are probably effective but never have been well
tested. But it shouldn’t be all in large clinical trials. I would agree
with that.

The only thing I would really like to take issue with is the notion
that Dr. Haley is raising about stress. I think all of us—I am a
“stress researcher,”—I think that how you define stress to a large
extent dictates what you really think are causing these illnesses,
and what kinds of things are capable of triggering these illnesses.

Most people who study stress feel that there are stereotypical re-
sponses that the body has to physical trauma, certain types of
drugs and toxins, emotional stress and a whole lot of ferent
kinds of exposures that we come across in our environment. That.
is certain] my point of view and that is the way I use the term

“stress.” Not in a pejorative sense, not in an emotional sense, but
rather the issue is that is the only’ word we have, and I would love
for someone to come up with a better word, because I am stuck
with it. I would rather not be pigeonholed into thinking this is an
emotional or psychological disease because I think anything but
that. So I thin! E we should be careful.

Mr. SHayYs. You could say scared to—


128

command here and on the communications between the relevant
oversight responsibilities here, to make sure that we can fix the re-
sponsibility for any unforeseen consequences, shall we say, that
might be experienced by those who are now in the Persian Gulf.
Because I think the question that many Americans are going to be
concerned about: Their sons and daughters who are there now, are
they going to be returning with symptoms and will they be exposed
to the same kinds of toxins, and can we be assured that they won’t
be aa en toxic drugs?
ir. SHays. And the reason why that question is important is, we

want someone to take ownership.

Mr. Kucinicu. Right.

{The information referred to follows:]


134

Mr. SHays. When the FDA allowed the Department of Defense
to use pyridostigmine bromide, PB, two requirements, one, they tell
the soldiers, and two, they keep records. They didn’t tell all the sol-
diers and they didn’t keep any records.

Ms. WInEGar. Right.

Mr. SHaAYsS. Nobody wants to take ownership.

Mr. Kucinicu. Thank you very much, Mr. Chairman, because
that’s a very important point; that is that, you know, the Depart-
ment of Defense had a so-called honest commitment to the FDA not
to give experimental drugs to soldiers without their consent and
then we found——

Mr. SHAYS. They couldn’t consent. They were ordered to.

Mr. KucInicu. They were ordered to, right.

Mr. SHAYS. They were just to be told that they were taking an
experimental drug.

ir. KUCINICH. Thank you.

Thank you, Mr. Chairman. Thank you.

Mr. Suays. Thank you. At this time, the Chair would call on Mr.
Sanders.

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

What I would like to do, I am going to go back to the report that
the committee published, because I was very impressed by it, and
I would like to ask Dr. Feussner to comment on some of the state-
ments that I am going to read you.

This is a statement that was made by Dr. Harold—Dr. Howard
Ernovitz. This is what he says, he testified before this committee
and he said, quote,

Recent studies have shown that prolonged and aggressive antibiotic therapy ap-
pears to abate many of the symptoms associated with Gulf War syndrome. Usually
the therapy takes longer than ordinary treatments, ie., 6 to 9 weeks instead of less
than 3 weeks. In many cases, the symptoms return when the therapy is discon-
tinued. . .
et cetera.

He has a thought about a therapy. My understanding is that you
have said there is no active treatments; trials are now being under-
taken. What do you think about Dr. Ernovitz’ theory? Are we work-
ing on that?

Dr. FEUSSNER. Yes, sir. I think that an antibiotic treatment with
our preliminary information, an antibiotic treatment trial may be
warranted. The difficulty with an antibiotic treatment trial is to
target the antibiotic treatment to eradicate the offending organism.
From my perspective of the literature, the best bet at the moment,
the clearest hypothesis for testing may be the issue of mycoplasma
that Dr. Nicholson has raised. .

Mr. SANDERS. We have been talking about this for years. Now,
in the State of Vermont, I specifically asked the guys who were
hurting, and I said, listen, no one can guarantee any cures. But if
there were an experimental treatment that we are pretty sure was
not going to make you worse than you are today, would you be pre-
pared to undertake that? Every hand in the room went up.

Now, this guy is doing work. Are you prepared to come to the
State of Vermont and start this antibiotic therapy?

Dr. FEUSSNER. The antibiotics that are typically suggested are
not investigational agents and are FDA-approved agents.


189

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178

review of the scientific literature prior to 1990, all of the decisions to protect troops in the war
were based on the best science of the day.

1 think the explanation, as I said at the start, is that a policy formed early, and all
subsequent activity subtly, though inexorably, conformed to the policy. ‘The present inertia is
sustained by "Conservation of Belief."

Tam afraid that this force is still so strong throughout the research hierarchy of the VA,
the DoD, CDC and other branches of government that it will not be overcome soon. No case
definition will be formulated. No epidemic investigation will be undertaken, Resources will
be spent on basic research into "stress" and on statistical and clinical comparisons of samples
of the deployed and nondeployed heedless of such biases as the “healthy-warrior effect," and
they will show nothing. Some productive research in experimental animals will demonstrate
the mechanisms of neurotoxic damage from chemical nerve agents and other chemical
combinations, and this will translate into protecting troops in future deptoyments—though
without directly challenging The Policy. But intramural government research and government-
funded extramural research will not come to bear on the Gulf War syndrome.

Moreover, I am pessimistic that any help will come from the elite scientific community
‘who will sit on government oversight committees and study sections for grant peer review. I
think they are by and large equally convinced of the stress theory, and unconsciously
conforming to The Policy, will not press hard enough to slow the current inertia.

‘What I am saying is that the problem is not with the structure of government research
or funding mechanism, or with the ill intentions of the government people and the outside
scientists. It is that there is a thoroughly ingrained Policy that is driving every person, every
study design, and every grant decision. ‘The problem is not structure, but inertia. And that
will not be fixed easily or soon.


14

No changes to the regulation are required in this regard. At the time the
determination is requested that informed consent is not feasible in a particular military
combat exigency, DoD should provide its plan for the dissemination of information.

(€) Should the rule address what constitutes adequate record-keeping
and adequate long term follow-up of individuals who receive investigational products?
If so, in what way?

The rule need not more specifically address record-keeping for the use of
investigational products. Issues of record-keeping and follow-up are already covered in
existing FDA regulations and guidelines, including the rules for the treatment use of
INDs. DoD and FDA should work toward a mutually satisfactory resolution of
feasible record keeping requirements. This work can take account of ongoing DoD
initiatives to develop automated record keeping and immunization tracking systems.
These should facilitate record keeping and follow-up for approved products and INDs,
even in operational settings.

() Should the rule contain additional procedures to enhance
understanding, oversight, and accountability? If so, what are these procedures?

DoD believes internal military procedures for understanding, oversight, and
accountability have been and will continue to be strengthened. These matters,
however, are separate from the decisive factors pertinent to the issue of the feasibility
of informed consent under certain military combat exigencies.

(g) Should the rule contain additional procedures to track
noncompliance?

Validation of compliance is an important matter for DoD to assure. However,
no changes in the regulation are needed concerning this matter.

Issue B: When is it ethical to expose volunteers to toxic chemical and biological agents
to test the effectiveness of products that may be used to provide potential protection
against those agents?

The products under development are to be used to protect service members
against lethal exposure to chemical and biological warfare agents. It is never ethical to
expose volunteers to such lethal amounts of these agents in order to test the potential
effectiveness of pre-treatment, treatment or prophylactic products.

Dose or concentration ranging studies are normally required for new or new-
indication studies of drugs or biologics. Because response to treatment of sub-lethal
doses of chemical or biological agents (weapons) could not be extrapolated to predict
response to higher doses, a lethal dose would be necessary to test the efficacy of the
Protective drug or biologic. If lethal doses were given to volunteers, a 100% effective


32

Although the investment in GWVI has already provided some meaningful results, the full
impact of research often cannot be fully assessed for years after awards are made. Funds
appropriated for GWVI research are typically placed on contracts 9 to 12 months after
appropriation. This reflects the average time to: complete the solicitation, advertise it to the
scientific community, prepare research proposals, conduct independent peer review, develop an
investment portfolio by the RWG, accomplish regulatory compliance review and negotiate
awards Once an award is made, studies usually take between 3 and 5 years to complete. The
final results are normally published in the scientific literature several months after completion of
the contract or grant. These individual studies eventually merge into a body of knowledge that
may be used for the definitive prevention and treatment of an illness, as well as advancing
scientific hypotheses.

The DDR&E took several actions during the past year to increase the visibility and oversight
of Defense research efforts on GWVI, as well as to facilitate program integration with the RWG.
These actions include:

ist, taking steps to establish a single Defense Program Element and project in FY99,
with 1998 being the transition year, for a dedicated project for DoD GWVI-specific
research. Currently, Defense research on GWVI is supported under multiple Defense-
wide and Army RDT&E program elements. Establishment of a single Defense line for
GWVL-specific research should improve DoD oversight and expedite Congressional
review since program accomplishments, plans and resource information will appear as a
single program on the RDT&E Budget Item Justification Sheet (R-2 Exhibit)

Second, chartering a Working Integrated Process Team (WIPT) on Deployment
Toxicology in November 1997. The purpose of the WIPT is to review current
deployment toxicology initiatives and develop a recommendation for the ASBREM
regarding appropriate DoD-level sponsorship and oversight of related policy issues,
doctrinal matters, and requirements generation. This initiative complements, supports,
and builds on DoD Directive 6490.2, “Joint Medical Surveillance,” and DoD Instruction
Number 6490.3, “Implementation and Application of Joint Medical Surveillance for
Deployments,” which were both issued in August 1997 by the Deputy Secretary of

liness), respectively.
initiatives are essential to provide the new technologies, doctrine, training and
operational practices necessary for protecting the force during future deployments.

© Third, incorporating review of DoD-sponsored GWVI science and technology in the
annual TARA process. This review is utilized by the DDR&E to obtain advice and
recommendations and utilizes the expertise of outside reviewers and the DSTAG.

Summary of GWVI Research Results
The details of the RWG coordinated and integrated research efforts of DoD, VA, and DHHS.

will be provided in the DoD’s Report to Congress and in the PGVCG-RWG's Annual Report to
Congress that will be submitted by the Secretary of Veterans Affairs. At this point, I will simply


103

threatened and servicepersons taking protective agents more greatly
endangered. They would be additionally endangered if they attempted
to help these servicepersons.

Fortunately, the degree to which these agents would protect
servicepersons from the effects of chemical and biological weapons
was never tested in the Persian Gulf. Yet, investigations following
the war have indicated that Iraq had these weapons ready for use.
It may have been only because Iraq falsely believed that the US
would retaliate with nuclear weapons that Iraq decided not to use
them. Our information regarding the weapons Iraq could have used
was accurate. For example, Iraq was prepared to deliver botulism,
a highly lethal disease, by missile attack. Botulism vaccine was
one of the protective agents given to servicepersons.

Thus, this chilling question remains. What would have happened
if Iraq had used these weapons and U. S. forces had not had as much
protection as possible? The grim outcome which can be imagined
supports the wisdom of the ethical judgements actually made. It
suggests as well, several new needs, such as to ineure that
servicepersons are protected as much as possible in the future and
to establish means by which other countries’ forces, captured enemy
servicepersons and civilians can be protected as well. These
initiatives may go beyond the scope of this discussion, but,
hopefully, will be among the ethically important outgrowths of this

meeting.


4. Medical Support:
a. Identify (name and address) the emergency medical care facility that provides local
support to the organization, and describe any specific treatment resources for hazards
unique to the proposed research. Identify organizational personnel (office and ttle(s))
who have been designated as points of contact for advanced treatment resources and
consultation.
b. Describe the routine medical monitoring/occupational health program and process by
which the results of the program are reviewed. Identify the program provider (office and
individual's official title) and frequency of monitoring
¢. Describe any immunization program required in association with the proposed

5. Loss Control: Describe the security provisions, access restrictions, and/or administrative

controls for the materials involved in the proposed research.

DATE OF PREPARATION:

PREPARED BY:

23


164

several researchers told us that they had considered it pointless
to pursue hypotheses that the symptoms may have been associated

with exposures to chemical weapons.

When we asked investigators responsible for federally funded
epidemiological research how they were collecting data on the
various elements to which Gulf veterans may have been exposed, they
indicated that they had no means other than self-reports for
measuring most of these elements. This reliance on self-reports
was not much less for elements such as vaccines, for which the

opportunity for record keeping clearly existed.”

Two problems are associated with reliance on self-reports for
exposure assessments. First, recalled information may be
inaccurate or biased after such a long time period; that is, some
veterans may not remember that they were exposed to particular
factors, while others may not have been exposed but nonetheless
inaccurately report that they were. Information also may be biased
if, for example, veterans who became sick following the war
recalled their exposures earlier, more often, or differently from
veterans who had not become sick. Second, there is often no
straightforward way to test the validity of self-reported exposure
information, making it impossible to separate bias from actual

differences in exposure frequency.

ay

War, but Mixed Results in Bosnia (GAO/NSIAD-97-136) .
16


64

Mr. Towns. Dr. Gerrity.

Mr. GERRITY. I don’t have a prepared statement.

Mr. Towns. No prepared statement. Thank you.

Let me begin then by asking, can you tell us what kind of coordi-
nation efforts are in place for research, as well as funding, at this
particular time? :

Dr. FEUSSNER. You mean the process that is involved from soup
to nuts, the identification of a part, or all the way through?

Mr. Towns. All the way through.

Mr. FEUSSNER. Yes, sir.

Typically what happens when inputs are received or are offered
to the Persian Gulf Research Working Group, one of the depart-
ments will take a lead in developing some ideas about how the re-
search is to be approached. Then that is discussed during the com-
mittee meetings. BAAs, broad area announcements, are made.
Then, DOD releases the request. In the VA, these are called re-
quests for applications, RFAs. Both BAAs and RFAs are typically
time-limited requests so that you might announce one of these at
time X and then have the proposals submitted within 90 to 120

days.

There is another mechanism that is used. DOD has used BAAs
that are open-ended. The VA has yet another mechanism called
program announcements, which are open-ended announcements in
priority research areas.

Once the nature of the research solicitation is clear, discussed
among VA, DOD, NIH, CDC, et cetera, the programs are officially
announced. Investigators then may. respond to those announce-
ments with written grant proposals. Then those proposals are re-
viewed and the review, a scientific review, is nested within the
originating department, so that DOD would assume responsibility
for having proposals submitted to DOD externally reviewed; VA,
the same; CDC, NIH, likewise.

After the external peer review, the grants are rank-ordered in
terms of priority, the best score being one, so that a grant proposal
that would be rank-ordered on scientific merit as one would be vir-
tually perfect, through a score of five, which would be very imper-
fect. Then the approved proposals with high-priority scores undergo
a secondary review by a subcommittee of the Persian Gulf Re-
search Working Group for relevance to see if the prioritization
needs to change for the scientifically approved research projects.
That again gives a chance for combined and coordinated input from
the several membership groups in the Research Working Group.
Then, recommendations are made back to the originating depart-
ment for funding decisions.

Mr. Towns. Thank you. The reason I mentioned this is because
we have asked about the inclusion of members of the medical com-
munity who may have unorthodox or, for lack of a better word,
novel theories. Have you managed to include those views in the Re-
search Working Group?

Dr. FEUSSNER. The answer to that question is yes. In addition to
the standing memberships of the Research Working Group that we
alluded to earlier, the Research Working Group has had on the
order of 80 to 85 additional ad hoc members called in at various
times to provide their expertise. Over the course of the last several


203

are working in a way presumably that no one else in the country
is working; is that correct?

Dr. HALEY. I don’t know.

Mr. SANDERS. That is one of the problems we have now, isn’t it?
You develop your own approach.

Dr. HALEY. Let me comment, because I think—see, I don’t think
you want to start right now, as I think maybe the VA is being pres-
sured to do, and do a huge clinical trial with, you know, 500 or
1,000 sick Gulf war veterans and randomize them into treatment
and placebo groups. The chances of that getting anywhere is zero.
What you want to do is stimulate, and maybe this is what they are
doing, I don’t know the details of that trial yet, but maybe what
we need to do is stimulate a number of researchers who have ac-
cess to these people who really care for them on a daily basis and
can understand what these symptoms are, to come up with a whole
bunch of little trials and what I call phase 2 trials, not definitive
trials. What we are doing is not something that, no matter what
we find, is 5 Boing to be definitive. What we are doing is, you might
call it, an N of one trial or an individual patient trial. Each patient
is his or her own control. This is a very preliminary type of trial
to get some idea is there a medication that just looks like it is daz-
zling; but that doesn’t mean that some of the things that don’t
show up are going to be given up. But we may be lu and iden-
tify something. Chances are we probably won’t, but if 100 other
people were doing that, pretty soon somebody would come up with
something that really looks good.

Mr. SANDERS. All that I was suggesting is that we should all
know that there are 100 people doing it and we should know the
results: this one failed, partial success or really great, and amplify

at.

Dr. HALEY. It is crucial, though, and this was mentioned by the
other panel; in doing a trial like that, though, you must have ways
of measuring the end points: How did people respond? You can’t
just ask them. Many of the doctors out there who feel like they are

etting really good results have not measured, so they don’t know.
y just are very enthusiastic that their patients like what they
are doing, but they haven’t measured really an effect.

Mr. SANDERS. I agree, but you agree that we should have defini-
tive information about what is going on?

Dr. HaLey. Yes. To do all of the things that I just mentioned,
even this little informal preliminary trial that we are doing is very
complex. It has taken us 6 months to get it off the ground, the
funding has been denied twice.

Mr. SANDERS. We have 750,000 people who are hurting and we
spend $1.5 billion for the B-2 bomber, so I think we have the re-
sources to do it.

Dr. HaLey. Just don’t feel that this is something similar to do.
I know Dr. Clauw is struggling with this. It is very complex to do
it right, so that you don’t injure people with medication and so
forth, and that you measure accurately.

Mr. SANDERS. Mr. Chairman, I just wanted to ask Dr. Sharma.

Mr. SHARMA. I just wanted to mention that we have done studies
called cross-syntheses to measure exactly the kinds of problem you
are facing with Gulf war veterans. This is an alternative to doing


148

formation from actual differences in the frequency of exposures. As
a result, findings from these studies may be spurious or equivocal.

Fifth and last, classifying the veterans’ symptoms and identifying
the illnesses have been difficult. From the outset, the symptoms re-
ported have been varied and difficult to classify into one or more
distinct groups. Moreover, several different diagnoses might pro-
vide plausible explanations for some of the specific health com-
plaints. It has thus been difficult to develop one or more working
case definitions to describe veterans’ undiagnosed complaints.

Given these methodological limitations which are faced in the ep-
idemiological studies and because of the numbers of veterans who
experienced illnesses that might be related to their Gulf war serv-
ice, we recommended in our report that the Secretary of Defense,
with the Secretary of the VA, give greater priority to research on
effective treatment for ill veterans and on low-level exposures to
chemicals and other agents, as well as their interactive effects, and
less priority to further epidemiological studies.

Mr. Chairman, that concludes my prepared remarks. I will be
happy to answer any questions you may have.

tthe prepared statement of Ms. Heivilin follows:]


35

and after leaving military service. These data could be used to detect the appearance of
novel or unanticipated health risks and to quickly deploy assets to collect and assess data
relevant to any newly identified threats.

‘Conclusion

Let me conclude by noting that it has not yet been 5 years since formation of the PGVCB-
RWG to coordinate Federal research into the health consequences of service in the Persian Gulf
War. The genuine concern and recognition of the magnitude and consequences of the challenges
before us are reflected by our commitment to work in a productive and cooperative manner that
exploits our individual Departments scientific strengths and unifies them into a productive,
responsive and fully integrated research effort, the RWG Working Plan. As Uhave alluded, the
path of science is difficult, challenging, expensive and time consuming. Easy and complete
solutions to complex health problems are exceptionally attractive but extremely rare. This truth is
especially obvious to those who suffer the consequences of prolonged, often incapacitating,
ilinesses of uncertain or unknown origins and for whom medical science offers litle in the way of
long-lasting relief or a cure.

We are committed to sustaining a sound and responsive RWG Working Plan against which
scientifically meritorious proposals will be evaluated for relative programmatic merit.
Historically, the match of scientific merit and program needs has been the foundation upon which
‘our National leadership in medical science has been built. I am unaware that there are either
reliable alternative means or compelling reasons for risking our potential for meaningful progress
by challenging or changing that proven formula for success.

Thave summarized our success and findings to date and highlighted new directions the DoD and
our Federal partners are taking to resolve GWVI and prevent similar illnesses among our service
men and women as a consequence of future deployments. The challenges are great and while
there may be no quick solutions, we are committed to responsible and aggressive pursuit and
resolution of these problems


67

‘THE ASSISTANT SECRETARY OF DEFENSE
WASHINGTON, D.C, 20301-1200

Michael A. Friedman, M.D. wt 28 1907
Lead Deputy Commissioner

Food and Drug Administration

Department of Health and Human Services

Rockville, Maryland 20857

Attn: Documents Management Branch (HFA-305)
Re: Docket No: 90N-0302

Dear Dr. Friedman:

This lewer provides Department of Defense (DoD) comments on the July 31,
1997, Federal Register notice soliciting comments on the Interim Final Rule of
December 21, 1990, authorizing the Commissioner of Food and Drugs to determine
that obtaining informed consent for the use of investigational new drugs in certain
military combat exigencies is not feasible. We feel the prime objective should be to
allow medical personnel to use the best prophylactic and therapeutic products available
to protect military members against chemical and biological weapons and other
operational medical threats and to protect disaster response personnel and the public in
the event of domestic terrorism use of chemical and biological weapons We offer three
primary points in support of maintaining the "military combat exigency" rule.

1, We must keep faith with the President's commitment that "we will always,

always do everything we can to protect our own."

Consideration of the military combat exigency rule should be guided primarily
by the need to protect military forces. There are undoubtedly numerous compliance
issues concerning "investigational new drug” (IND) rules in military combat
operations, and many of these are indeed important. But they are secondary to the
primary issues of the life and health of military members in high threat situations. The
review of the interim final rule should start with a commitment to allow medical
personnel to use the best prophylactic and therapeutic products available to protect
military members against chemical and biological weapons and other operational
medical threats.

2. The need to “protect our own" extends to the threat of foreign and domestic

sm involving use of chemical or biological weapons against military personne! or

Khobar Towers. the World Trade Center, Oklahoma City, and the Tokyo
‘Subway are reminders of the need for preparedness against terrorism. The DoD is


190

Mr. Suays. Dr. Reeves.

Dr. REEvES. I am Dr. William C. Reeves, Chief of the Viral
Exanthems and Herpesvirus Branch, Division of Viral and Rickett-
sial Diseases, National Center for Infectious Diseases, Centers for
Disease Control and Prevention.

In November 1994, the Department of Veterans’ Affairs, the De-
partment of Defense, and the Pennsylvania Department of Health
requested that CDC conduct an independent investigation of a re-

rt of unexplained illness among Gulf war veterans in the 193rd
Pennsylvania Air National Guard Special Operations Group. Be-
tween December 1994 and May 1995, we studied veterans and non-
deployed personnel to document symptoms, develop a case defini-
tion, compare illness rates, clinically characterize the illness, and
identify risk factors.

Initially, 3,927 volunteers from four Air Force bases in Pennsyl-
vania and Florida, including the 193rd Air National Guard Special
Operations Group, were interviewed without restrictions as to
health or participation in the Gulf war. The veterans were inter-
viewed anonymously for symptoms, demographic and military char-
acteristics, and deployment history. Gulf war veterans, of whom
there were 1,164, reported all symptoms more frequently than non-
deployed personnel, of whom there were 2,763. We identified an ill-
ness defined by chronic fatigue, mood and cognition symptoms and
musculoskeletal pain. Forty-five percent of Air Force Gulf war vet-
erans were studied and 15 percent of nondeployed personnel met.
the case definition for illness.

Next, 158 volunteer Gulf war veterans from the 193rd Air Na-
tional Guard Special Operations Group, which included 13 severe
cases, 86 mild to moderate cases, and 59 noncases, as defined by
the initial 4-base survey, completed a detailed clinical epidemiology
questionnaire, had standardized physical and psychometric exams
and submitted blood, urine and stool specimens for laboratory stud-
ies.

Case subjects had significant decrease in function and well-being,
but illness was not associated with physical exam or laboratory ab-
normalities, or with exposure to any of the infectious agents that
we measured. Specifics of deployment or military characteristics
were not associated with illness.

In conclusion, we analyzed symptom data collected from all par-
ticipants and identified or defined an illness that closely resembles
chronic fatigue syndrome. Illness was 4 to 16 times more common
among Gulf war veterans. Illness rates for nondeployed were simi-
lar to those in civilian populations, and other than deployment to
the Gulf war, there were no unique risk factors.

Thank you for the opportunity to discuss this study of illness in
Air Force Gulf war veterans. I will be pleased to answer questions
you or other members of the subcommittee may have.

Mr. SHays. Thank you very much, Dr. Reeves. Let me ask you,
before we start, I am going to defer—I am going to tell you what
my question is and then I am going to call on Mr. Sanders before
you answer. I want to know where you agree and disagree with
each other and where you agree and disagree with the earlier
panel. That is what I am going to want to know, and I would love
you to think about that. I will yield to Mr. Sanders.


196

looking at cause up front, we can look at subsequent symptoms and
go back and look at causes.

Mr. SANDERS. But might we be able to prevent some suffering
today if we are able to tell me, stay away from this? Most of these
people, they didn’t even know that they have Gulf war illnesses,
they are just getting sick and they work in a certain climate every

day.

‘br. Haley, is that correct?

Dr. HALEY. Yes. One of the notable veterans that we are follow-
ing, every time he gets in an environment with automobile exhaust
or whatever, he takes a turn—this is his feeling, he takes a turn
for the worse. The problem is, he can’t avoid all of those things, so
we are really looking for that person for a medication that would
make them more resistant to these because in our modern society
it is just really hard. Now, they should be avoiding, to the extent
they can, but you just can’t avoid everything.

Mr. SANDERS. I understand. For some folks, some may not, they
may not even understand why they are getting ill.

Mr. SHARMA. One of the purposes of the epidemiological studies
is to develop the natural history of the disease. And the one that
Dr. Haley mentioned earlier, that CDC could have done an epi-
demic investigation; and what we do is to redevelop the course of
the illness as part of the investigation. Seven years our veterans
have been suffering but we really don’t know the natural progres-
sion of the disease, which way it goes, what is the order of the
symptoms as they are appearing in subsets or among all of them;
and at minimum, I think that is something that we could have
done. And I don’t see any studies, despite the fact that a large
number of them are epidemiological studies, that are trying to un-
derstand what is pone on with the veterans.

Mr. SANDERS. I am going to give the mic over to the chairman,
but I would like you to think about my next question which will
be, if you had a blank check, what would you do? Where would you
go from here? Mr. Chairman.

Mr. Suays. That is a very provocative question. Dr. Haley, I saw
you light up like a light bulb.

Dr. HAL EY. Is that an offer?

Mr. SHays. Where would you disagree with each other and where
would you disagree with the earlier panel? This isn’t petty debate
here, I just want to know—I need some definition to see where the
differences are, where we do have honest disagreements. I will
start again.

The previous panel, and I think most of you were here, you heard
what they said. What would you like to amplify or disagree with
the previous panel and what would you amplify or disagree with
the present participants here?

is. HEIVILIN. We absolutely think that looking at low-level
chemicals, the synergistic effects of low-level chemicals is a hypoth-
esis, that definitely needs to be studied. We have said that. I would
disagree with some of the members of that panel who didn’t seem
to think that that was a reasonable thing to do.

Mr. Suays. Dr. Haley.

Dr. HALEy. I would like to take real serious issue with the as-
sumption, almost the mantra, that stress has anything to do with


104

Mr. Towns. Mr. Chairman, I yield back.

Mr. Suays. Thank you.

Mr. Snowbarger.

Mr. SNOWBARGER. Thank you, Mr. Chairman. I apologize to you
and also to the witnesses that I was not able to be here for most
of your testimony. So I apologize if I am asking questions that you
feel like you have already answered, but if you would bear with
me, I would appreciate it.

One of the problems that has faced this panel and faces you in
this issue is the question of information that is available to you,
particularly exposure information; and it seems that without that
exposure information, at least accurate exposure information, that
we are spending millions of dollars on research here, and I am just
not confident that I know whether or not we are going to be able
to produce any results, much less accurate results.

guess, Dr. Feussner, if I could ask you, could you tell me what
studies are under way that you think are going to produce valid
definitions of what. Gulf war veterans’ illnesses are all about?

Dr. FEUSSNER. Well, that is a difficult question. I think your as-
sertion is correct. Highly problematic is the observation that there
are multiple potential exposures that occurred at multiple potential
times and in multiple potential combinations. It is not—I do not be-
lieve it is possible to specify who was exposed to what with any
precision. That causes difficulty in doing the research on two
fronts. Less desirable definitions of exposure must be used, for ex-
ample, in the VA mortality study, deployment to the Gulf versus
being active duty and not deployed to the Gulf.

That level of imprecision introduces noise into the assessment
and that requires large sample sizes of study patients followed for
a long duration of time to try to detect differences in those groups.

For example, I believe that, the mortality study that has now
had 4 years of followup may present useful information about
whether survival is different, whether disease-specific survival is
different in deployed versus nondeployed study subjects.

The other way I think that we can approach that, short of
human studies, is to look at animal studies where a research
project, for example, showed that pyridostigmine bromide does not
cross the blood-brain barrier, but when animals were exposed to
stressful situations, the stress modified the permeability of the
blood-brain barrier and that chemical was able to get across the
blood-brain barrier.

I think opportunistic efforts, for example, the collaboration with
the Japanese where they have known exposures and they can
study those exposures soon after they occurred, may provide us
some insights, but saying what causes this, how do we fix this, as
opposed to merely treating this are very nettlesome issues.

Mr. SNOWBARGER. Well, I guess the reason for my question is, we
are 3 years down the road from the time the initial studies were
begun. I mean, the problem showed up earlier than that, but we
didn’t start until 1994, or somewhere in that neighborhood; and
here we are almost 4 years later, and I am not getting any sense
of confidence that we are going to be able to do the studies that
are going to lead us to the right answers.


167

meaningful results within this type of research design. At the
same time, for the case definition to be relevant, it must fit the
symptoms described by an important portion of the group being

studied.

Sample Size

Most of the investigators we interviewed took steps to estimate the
size of the sample they would require to have a reasonable
expectation of detecting the effects of exposures to hazardous
substances. However, many other variables were involved in such
calculations, for example, the prevalence of exposures, some of
which were unknown at the time the studies were planned. Thus,

they had to make estimates within somewhat broad parameters.

Although steps were clearly taken to plan for an adequate sample
size, some investigators reported difficulty in locating subjects
due to factors beyond their control, such as the rate of referrals
from VA examination centers or the rate of identification of
subjects that fit highly specific case definitions. Moreover,
other studies, such as those on specific birth defects, required

extremely large samples.

19


126

Dr. FEUSSNER. Yes, sir.

Mr. KUCINICH. You know, in listening to your testimony, in read-
ing it and also in reading some background material, something oc-
curs to me. And maybe this question was asked before, but if it
wasn’t you could help elucidate this for all of us. If we don’t even
know what Gulf war syndrome is, then how can we protect the
troops who are out in the Gulf region right now?

Dr. FEUSSNER. Do you want to do that?

Ms. Winecar. I will try to give you a partial answer to that. I
think that one of the things that Dr. Feussner alluded to was the
fact that we need a lot more information; and I think that we have
taken some positive steps on being able to better track individuals
as to their location, being able to keep better records for what types
of medications they might be given, as far as their personal record,
their personal histories, and I think that the Department of De-
fense become attuned to the needs to be more exact in all the
records that we keep.

And so I think that this kind of data will certainly help us to as-
sess where these problem areas are and to make some positive cor-
rection, so that we don’t do that again.

I mean, we will never be able to get to the point where we can
test the hypothesis of every possible combination for every single
individual who may have inherent genetic differences or who may
have a history of exposures to some compound or the other. It is
an infinite number of possibilities, and I don’t think there is any-
thing we can do about that at the moment.

Dr. FEUSSNER. I think the short answer to your question is—and
there are some parallels here actually with Legionella and the
pneumonia caused by that organism. One of the earlier epidemics
there was the Pontiac fever in 1968, and not knowing what caused
that syndrome made it impossible to prevent subsequent exposures
and subsequent illnesses.

It is difficult to prevent something when you don’t exactly know
what the target is.

I think this committee and others have made recommendations
about chemical exposures, biological exposures, et cetera; and my
impression is that DOD is trying to deal with the ones they know
about. Dealing with the ones we don’t know about is——

Mr. KucINICcH. Well, but, Doctor, with all due respect, we have
a national policy now where we are sending thousands upon thou-
sands of troops to that region. And is your Department in contact
with the—those elements of the Defense Department that are de-
ploying these troops to immediately set into place certain analyses
and data collection and monitoring and means by which the Amer-
ican people can be assured that their sons and daughters are not
going to be exposed to harm from a syndrome which has not yet
been clearly identified, let alone harm from the combat which we
hope—which we hope never comes?

Dr. FEUSSNER. Well, again, the short answer to that question is
yes. And I think that——

Mr. Kucinicu. Tell me how. You know, the—my short rejoinder
is how? How?

Ms. Winecar. How are we in communication or how are we—


45

because information bearing on your health may be required to be reported to appropriate
medical or command authorities.

j. The following statement must be incorporated into the consent form: You are authorized
all necessary medical care for injury or disease which is the proximate result of your
participation in this research. The U.S. Army requires that this institution provide such
medical care when conducting research with private citizens, Other than medical care that
may be provided (and any other remuneration specifically stated in this consent form), there
is no other compensation available for your participation in this research study; however, you
understand this is not a waiver or release of your legal rights. (This statement must be in all
consent forms, regardless of risk level of the study.)

k. Provide the subject an explanation of:

(1) Whom to contact for answers to pertinent questions about the research, and
whom to contact to report research related injuries. The principal investigator should
be listed as the contact. This information should include complete telephone
number(s) and address(es).

(2) Whom to contact to answer questions about research subject's rights. The
Institutional Review Board (IRB) chairman and/or the legal office of the contracting
organization should be listed as the contact. This information should include
telephone numbers and addresses,

|. Include a statement that explains that participation is voluntary, that refusal to participate
will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that
the subject may discontinue participation at any time without penalty or loss of benefits to
which the subject is otherwise entitled.

m. If blood, tissue or body product samples will be drawn in the study for the express
purpose of storing for possible future use in another protocol, the following statement must
be included "I understand that there is a possibility that the [blood, tissue, body fluids«specify
what type] which I am providing under this study may also be used in other research studies
and could potentially have some commercial applicability." If, indeed, it is anticipated that the
samples donated by the subject will be used in other studies, an additional consent form must
be prepared for signature by the subject which states “I voluntarily and freely donate any and
all [blood, tissue, body fluids«specify what type] to the U.S. Government and hereby
relinquish all right, title and interest to said items." The title of the study should be inserted at
the top of the form.

n. Any additional costs to the subject must be clearly indicated.
©. Ifapplicable, the following must be included "In order to participate in this study, you

should have avoided becoming pregnant from the first day of your most recent menses. A
negative pregnancy test does not absolutely prove that you are not pregnant. Regardless of


It is important to distinguish between biomedical and
behavioral research, on the one hand, and the practice of
accepted therapy on the other, in order to know what
activities ought to undergo review for the protection of
human subjects in research.

For the most part, the term practice" refers to
interventions that are designed solely to enhance the well-
being of an individual patient or client and that have a
reasonable expectation of success. The purpose of medical
or behavioral practice is to provide diagnosis, preventive
treatment or therapy to particular individuals. By
contrast, the term "research" designates an activity
designed to test an hypothesis, permit conclusions to be
drawn, and thereby to develop or contribute to generalizable
knowledge. . .

When a clinician departs in a significant way from
standard or accepted practice, the innovation does not, in
and of itself, constitute research.

The rule itself makes clear that the only purpose is
treatment, and that there is no research purpose in the use of
INDs in military combat exigencies. Again quoting the primary
standard in the regulation:

‘The Commissioner may find that informed consent is not
feasible only when withholding treatment would be contrary
to the best interests of military personnel and there is no
available satisfactory alternative therapy.

21 CFR § 50.23(d)(1). Nothing in the regulation even hints that
the special authority is available if the military's purpose is
to conduct research. One might suggest that the use of an IND
for treatment purposes constitutes what the Belmont Report refers
to as a departure from accepted practice. The same might be said
for the common physician practice of off-label prescribing. But
as the Belmont Report makes clear, this does not, as an ethical
matter, convert a treatment purpose and effect into a research
purpose or effect.

Another example in which a significant departure from
standard clinical practice is not considered "research" is the


hypotheses; identify potential new research approaches; review research concepts as they
are developed; collect and disseminate scientifically peer-reviewed research information;
and ensure that appropriate peer review and oversight are applied to research conducted
and sponsored by the federal government.

‘The biomedical research programs in VA, DoD, and HHS have well established
management structures for science policy formulation and the solicitation, scientific peer
review, and funding of research projects. The coordination and management of this large
research effort on Gulf War veterans’ illnesses required the establishment of an overall
research policy framework linking each Department's research management hierarchy.
To provide this linkage, in 1993 VA, DoD, and HHS formed the “Persian Gulf
Interagency Research Coordinating Council”. By January 1994, when the Secretaries of
VA, DoD, and HHS formed the Persian Gulf Veterans Coordinating Board (PGVCB), the
Research Coordinating Council became the Research Working Group (RWG) operating
under the auspices of the Coordinating Board. Because of the potential link between
environmental factors and Gulf War veterans’ illnesses, the Environmental Protection
Agency was asked to be a member of the Research Working Group.

‘An important function of the RWG is programmatic review and recommendation
to funding agencies of research proposals that have been competitively peer reviewed. The
RWG works collectively with VA, DoD, and HHS to elucidate agency-specific funding
mechanisms to support research in those identified areas. For a specific research funding
activity, the responsible funding agency works with and through the RWG to develop a
targeted solicitation for research. Proposals that are submitted to the funding agency in

response to a solicitation are scientifically peer-reviewed using agency-specific peer-


GULF WAR VETERANS’ ILLNESSES: THE
RESEARCH AGENDA

TUESDAY, FEBRUARY 24, 1998

HOUSE OF REPRESENTATIVES,
SUBCOMMITTEE ON HUMAN RESOURCES,
COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT,
Washington, DC.

The subcommittee met, pursuant to notice, at 10 a.m., in room
2154, Rayburn House Office Building, Hon. Christopher Shays
(chairman of the subcommittee) presiding.

Present: Representatives Shays, Snowbarger, Towns, Kucinich,
Allen, and Sanders.

Staff present: Lawrence Halloran, staff director; Robert A. New-
man, professional staff member; and Cherri Branson, minority
counsel.

Mr. Suays. I call this hearing to order and welcome our wit-
nesses and our guests on this very important hearing, and welcome
my colleagues, Mr. Towns and Mr. Sanders, as well.

In our oversight report on Gulf war veterans’ illnesses, adopted
without dissent by the full Government Reform and Oversight
Committee in November, we found the Federal research effort had
been blind to scientifically important but politically inconvenient,
hypotheses about neurotoxic exposures. The committee rec-
ommended shifting control of the research agenda to an agency free
of the institutional biases and doctrinal restraints we found hob-
bling the joint Veterans’ Affairs and Defense Department program.

Today, we pursue and amplify that recommendation with an in-
depth review of the Research Working Group of the Persian Gulf
Veterans Coordinating Board, the interagency body now respon-
sible for the evaluation and selection of the epidemiological, clinical
and basic research critical to the health, and hopes, of sick veter-
ans. The process and product of their work will tell us where we
have been, where we are, and where we need to go in studying the
causes and cures of Gulf war veterans’ illnesses.

The issue today is not blame for false starts and past failures.
The issue today, and every day until the discovery of effective
treatments, is how to focus a 6-year-old, $115 million research pro-
gram that appears to confuse motion for progress, quantity for
quality, and breadth for depth. The current agenda, although lately
pointed toward more probable and promising theories, still projects
a diffused, confused path that stretches well over the millennial ho-
rizon.

wD


150

(3) in contrast, the private sector pursued research on the health
effects of low-level exposures to certain chemical warfare

agents or industrial chemical compounds;

(4) government research used an epidemiological approach, but

little research on treatment was funded; and

(5) most of the ongoing epidemiological research focusing on the
prevalence or causes of Gulf War-related illnesses will not
provide conclusive answers, particularly in identifying risk
factors or potential causes due to formidable methodological

and data problems.

BACKGROUND

U.S. troops were reportedly exposed before, during, and after the
Gulf War to a variety of potentially hazardous substances. These
substances include decontaminating and protective compounds used
without proper safeguards (particularly decontaminating solution 2,
or DS2, and chemical agent resistant coating); diesel fuel used as
a sand suppressant in and around encampments, fuel oil used to burn
human waste; fuel in shower water; and leaded vehicle exhaust used
to dry sleeping bags. Other potential hazards included infectious
diseases (most prominently leishmaniasis, a parasitic infection);
pyridostigmine bromide and vaccines (to protect against chemical

and biological weapons); depleted uranium (contained in certain


42

g. The USAMRMC may inspect contractor records concerning the use of humans as
research subjects. .

h. The Human Use Review and Regulatory Affairs Division (HURRAD) is the office to
which principal investigators are to report any research related illnesses or injuries which have
occurred as a result of a subject's participation in an investigational drug/device study
sponsored by the USAMRMC.

i. Itis the policy of the USAMRMC that whenever the use of volunteers exists in
USAMRMC sponsored research, data sheets are to be completed on all volunteers for entry
in the USAMRMC's Volunteer Registry data base. The intent of the data base is twofold:
first, to readily answer questions concerning an individual's participation in research
‘conducted or sponsored by the USAMRMC; and second, to ensure that the USAMRMC can
‘exercise its “duty to warn." The "duty to wam" is an obligation to ensure that research
volunteers are adequately informed concerning the risks involved with their participation in
research, and to provide them with any newly acquired information that may affect their well-
‘being when that information becomes available. The duty to wam exists even after the
volunteer has completed his or her participation in research. To accomplish this, a system
must be established which will permit the identification of volunteers who have participated in
research conducted or sponsored by the USAMRMC. The data base must contain items of
personal information, for example, name, Social Security Number, etc., which subjects it to
the provision of The Privacy Act of 1974. References: Federal Acquisition Regulation (FAR)
Protection of Privacy and Freedom of Information at Part 24; Privacy Act clauses of the
FAR, Privacy Act Notification at 52.224-1, and the Privacy Act at 52.224-2. For each
subject enrolled in a USAMRMC-sponsored study, a Volunteer Registry Data Sheet
(USAMRMC Form 60-R, attached), is to be completed, The principal investigator is to
complete Part A of Form 60-R; after which, Form 60-R is to be provided to volunteers for
completion at the time of consent. The information collected is then sent to the Human Use
Review and Regulatory Affairs Division (HURRAD) upon completion of the research or
upon expiration/termination of the contract, whichever occurs first. Data sheets collected on.
volunteers participating in task orders or subelements of the overall effort are to be submitted
to the HURRAD upon completion of each task order or subelement. The information is
stored in the USAMRMC Headquarters data base for a minimum of 75 years. Information
stored in the Volunteer Registry data base will be disclosed in accordance with Army
Regulation 340-21 (the Army Privacy Program), and the Privacy Act of 1974, Upon written
or oral requests, persons on whom data is collected, or a specific designated agent or legal
guardian may have access to the record pertaining to that individual contained in the
Volunteer Registry data base. Only authorized staff of the HURRAD may have access to
information entered in and information selected from the Volunteer Registry data base.

4, Elements of Informed Consent. In seeking informed consent, the following information shall
bbe provided to each subject:

a. State the title of the study and location (specify address) where it is to be conducted.

33


161

exposures to low levels of organophosphates.'? It further linked
the veterans' illnesses to exposure to combinations of chemicals,
including nerve agents, pesticides in flea collars; DEET and highly

concentrated insect repellents; and pyridostigmine bromide tablets.

Finally, research that we reviewed also indicates that agents like
pyridostigmine bromide, which some Gulf War veterans took to
protect themselves against the immediate, life-threatening effects
of nerve agents, may alter the metabolism of organophosphates in
ways that activate their delayed, chronic effects on the brain.”
Moreover, exposure to combinations of organophosphates and related
chemicals like pyridostigmine or DEET has been shown in animal
studies to be far more likely to cause morbidity and mortality than

any of the chemicals acting alone.”

YR. W. Haley et al., “Is There a Gulf War Syndrome? Searching for
Syndromes by Factor Analysis of Symptoms,"

, vol. 277 (1997), pp. 215-222; R. W. Haley et
al., ‘"Evaluation of Neurologic Function in Gulf War Veterans: A
Blinded Case-Control study,"

, vol. 277 (1997), pp. 223-230; and R. W. Haley et al.,
‘Self-reported Exposure to Neurotoxic Chemical Combinations in the
Gulf War: A Cross-sectional Epidemiologic Study,"
American Medical Association, vol. 277 (1997), pp. 231-237.

“Cc. N. Pope and S. Padilla, "Potentiation of Organophosphorus
Delayed Neurotoxicity," i
Health, vol. 31 (1990), pp. 261-273.

M, B. Abou-Donia et al., “Increased Neurotoxicity Following
Concurrent Exposure to Pyridostigmine Bromide, DEET, and
Chlorpyrifos," Fundamental of Applied Toxicology, vol. 34 (1996),
pp. 201-222. and M. B. Abou-Donia et al., "Neurotoxicity Resulting
From Coexposure to Pyridostigmine Bromide, Deet, and Permethrin,”
Journal of Toxicology and Environmental Health, vol. 48 (1996), pp.
35-56.

13


3

‘The scope of the rule should not be narrowed. 11 should be broadened in two
ways. First, it should be explicit that military operational exigencies other than combat
are covered within the scope of the rule. For example, protection against a terrorist
attack, such as that at Khobar Towers last year, or an endemic disease threat in a
peacekeeping or humanitarian operation might meet the criteria of the rule and should
be covered. Second, the issue of medical countermeasures against the threat of
domestic terrorism involving chemical or biological weapons should be considered.

A.(8) If the rule were to be re-proposed:

(@) Should there be a requirement that DoD’s proposed use of
investigational products(s) be approved by an IRB that is independent of DoD? If so,
why should DoD be held to a requirement not imposed on other institutions, and what
Should be the requirement for that independent IRB? Can this be accomplished without
compromising military or national security? -

Under the law, the chain of command for military operations "runs — (1) from
the President to the Secretary of Defense; and (2) from the Secretary of Defense to the
commander of the combatant command." 10 U.S.C. § 162. The Department of
Defense does not support the diversion of command responsibility to a review board.
It should be noted that the use of the military combat exigency rule requires a
determination by the Commissioner of Food and Drugs, who is independent of DoD.

®) Should the authority to make the “feasibility determination ” (i.e.,
whether obtaining informed consent is “not feasible”) under the interim rule be vested
in persons or entities other than the Commissioner of FDA?

The Commissioner of the FDA is the appropriate official for the feasibility
determination.

(c) Should the rule be more specific in describing the information that
must be supplied to military personnel, or should FDA have wide latitude to make such
determinations on a case-by-case basis?

‘The items of information to be provided to military personnel should be agreed
upon by the DoD and the FDA on a case-by-case basis. Information should address:
the nature and degree of peril against which the drug or vaccine is designed to protect;
safety and efficacy of the drug or vaccine; contraindications and side-effects; and
alternatives treatments.

(d) Should additional measures be taken to insure that information
required by FDA is effectively conveyed to the affected military personnel? If so, what
Should these measures be?


82

4

members are given the option of receiving tick-borne encephalitis
vaccine; members are free to decline the vaccine.

However, it is also possible that the best medical
countermeasures are products not approved by FDA for general
commercial marketing for the specific purpose involved, that
approval under the accelerated process is not practicable, and
that because of the nature of the threat and the lack of
alternatives, a failure to use a drug would endanger individual
members, others who rely upon them to carry out their respective
tasks, and the mission. The question becomes: what should be
done in such cases? In the preamble to the interim final rule,
the FDA answered the question:

- . DoD has the right and responsibility to make command
decisions that expose troops to the possibility of combat
and has the concomitant responsibility to protect the
welfare of these troops both individually and as a group. .

. FDA respects DoD's obligation and commitment to do
everything possible to protect military personnel who may be
exposed to potentially hazardous conditions. FDA further
appreciates that this protection may include medical
treatment or prevention with an investigational drug
considered necessary to protect not only the health of
individual soldiers but to ensure the welfare of the
remaining forces. . . . Since these individual soldiers may
be required to be exposed to combat, pexmitting them to
the_only available satisfactory protection against life-
interests and to the welfare of the other soldiers involved.

(Emphasis added. }

One might ask: why would military members decline
recommended drugs or vaccines under these circumstances? The
answer is that there could be many, many reasons. Individuals
might decide that it is unlikely that chemical or biological
weapons will be used, or that, if they are, protective gear will
be sufficient. They might have heard rumors of side effects or
“mystery illnesses" attributed to the drugs or vaccines. They
might not believe information from command authorities based on
disenchantment with circumstances particular or general. They
might have seen media coverage of statements from “public


GULF WAR VETERANS’ ILLNESSES: THE RESEARCH
AGENDA

HEARING

BEFORE THE

SUBCOMMITTEE ON HUMAN RESOURCES

OF THE

COMMITTEE ON GOVERNMENT
REFORM AND OVERSIGHT
HOUSE OF REPRESENTATIVES

ONE HUNDRED FIFTH CONGRESS
SECOND SESSION

FEBRUARY 24, 1998.

Serial No. 105-130

Printed for the use of the Committee on Government Reform and Oversight

oe

U.S. GOVERNMENT PRINTING OFFICE
49-511 CC WASHINGTON : 1998

For sale by the U.S. Government Printing Office
‘Superintendent of Documents, Congressional Sales Office, Washington, DC 20402

ISBN 0-16-057235-5



108

Mr. SNOWBARGER. Let me ask——

Mr. Suays. Excuse me. Dr. Gerrity, do you have something you
can add to this?

Mr. GERRITY. No. I just said that when you said that your
records indicated zero funding for 1998, that it is not going on. I
was just commenting that that is not necessarily the case, because
sometimes moneys are put into projects that are then funded out
of that initial pot of money over several years.

Mr. SNowsarGER. OK. Thanks for that clarification.

Did you get further information, Dr. Winegar?

Ms. WINEGAR. No, I don’t have any further information at this
point, but I will provide that to you.

Mr. SNOWBARGER. OK.

[The information referred to follows:]


182

ment illnesses such as Gulf war illness. These institutes should
consist of the best and brightest scientists from a number of dif-
ferent disciplines who will work toward a common goal of deter-
mining the causes and treatments of these conditions. It would
seem preferable to have such institutes housed outside of govern-
ment agencies, or else pressure from patient advocacy groups, com-
peting agencies, or even well-meaning politicians, may hinder the
important scientific effort that is necessary for these endeavors.
Thank you.

Mr. Suays. Thank you, Dr. Clauw.

[The prepared statement of Dr. Clauw follows:]


131

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159

depression, fatigue, and irritability. These delayed symptoms may

be permanent.

As early as the 1950s, studies demonstrated that repeated oral and
subcutaneous exposures to neurotoxic organophosphates produced
delayed neurotoxic effects in rats and mice. In addition, German
personnel who were exposed to nerve agents during World War II
displayed signs and symptoms of neurological problems even 5 to 10
years after their last exposure. Long-term abnormal neurological
and psychiatric symptoms as well as disturbed brain wave patterns
have also been seen in workers exposed to sarin in sarin
manufacturing plants." The same abnormal brain wave disturbances
were produced experimentally in primates by exposing them to low

doses of sarin.'?

Delayed, chronic neurotoxic effects were also seen in animal

experiments after the administration of organophosphates.'’ These

uF, H. Duffy et al., “Long-Term Effects of an Organophosphate Upon
the Human Electroencephalogram,"

Pharmacology, vol. 47 (1979), pp. 161-173, and P.R. Sidell,"Soman
and Sarin: Clinical Manifestations and Treatment of Accidental
Poisoning by Organophosphates," Clinical Toxicology, vol. 7 (1979),
pp. 1-17.

"J, L. Burchfield et al., "Persistent Effect of Sarin and Diodrin
Upon the Primate Electroencephalogram,”
Pharmacology, vol. 35 (1976), pp. 365-379.

PM. B. Abou-Donia, "Organophosphorus Ester-induced Delayed
Neurotoxicity,” Annual Review of Pharmacology Toxicology, vol. 21
(1981), pp. 511-548, and M. K. Johnson, "The Target for Initiation
of Delayed Neurotoxicity by Organophosphorus Esters: Biochemical
Studies and Neurotoxicological Applications," Review of

, vol. 4 (1982), pp. 141-212.

1




191

Mr. SANDERS. Thank you very much, Mr. Chairman. I want to
thank all of you for coming and thank you very much for all the
work that you have done. This has been an enormously difficult
and frustrating process, and some of you have been enormously
helpful in directing us.

Maybe let me start off with Dr. Haley, and I really appreciate
the work that you have done, and others may want to jump in. I
want to be very specific here.

Dr. Haley, if somebody walks into your office, they are suffering
from short-term memory loss, otherwise a healthy person, they
have mood swings, serious fatigue, gastrointestinal problems, per-
haps diarrhea, and they tell you that they can’t tolerate perfume
that their wife may wear, they are an automobile mechanic but
they can’t work around cars anymore because oil makes them sick,
cleaning agents make them sick, pesticides trigger off a reaction,
if that patient walks into your office, what conclusion do you reach?

Dr. EY. Let me say if that person walked into my office 5
years ago, I would have said this is a person with some psycho-
logical problem, and I think they are either faking or trying to get
money or something. Now that I have seen that in literally hun-
dreds of Gulf war veterans, some of whom I believe have subcor-
tical, mild subcortical dementia that I think we have been able to
prove, I think these people, if they are Gulf war veterans and have
an exposure that is reasonable, I would suspect that they have sub-
cortical or brain stem injury, probably from exposures to chemicals
in the war. I would want to, if it was feasible from a financial
standpoint and so forth, I would want to do the right tests that
would show or rule out subcortical brain damage.

Mr. SANDERS. You have led me almost to the next question.

Mr. Suays. If I could interrupt, is there a test to do that?

Dr. HaLey. Oh, yeah. We published a whole paper showing that
audiovestibular tests—these are tests that test the reflexes of the
brain stem the answer is yes, there are.
| Mr, Suays. And you also testified at our last hearing on this
issue?

Dr. HALEY. Yes.

Mr. SANDERS. Dr. Clauw, do you want to respond to that?

Dr. CLAuw. I would just like to respond by saying those individ-
uals do walk into my office. In fact, at 2 o’clock I have 10 or 15
such individuals who never went to the Gulf war, who aren’t ex-
posed to some of the different things that we are talking about, and
again, we call these illnesses multiple chemical sensitivity, chronic
fatigue syndrome, fibromyalgia, in the general population.

I would be very careful about saying that these individuals have
dementia or have damage to their central nervous system. My view
is that they have dysfunction of their central nervous system, but
I don’t think this is clear that this is damage; that is, damage
being Something that is irreversible and can’t be treated or can’t

e fixed.

Mr. SANDERS. Thank you for both of your responses. Let me go
back to Dr. Haley, because I think the chairman asked the question
that I was about to ask.

If I walk into your office because I am concerned about AIDS,
you are going to give me a test, it is easily demonstrable whether


109

PERSIAN GULF VETERANS HEALTH RESEARCH
PROJECT UPDATE SHEET

PROJECT STATUS: Ongoing
PROJECT ID: DOD-13 DATE OF UPDATE: 30 September 1997
AGENCY: Department of Defense
PROJECT TITLE: Effects of Persian Gulf War Service on Military Working Dogs.
(Indicators of Human Disease from Persian Gulf War Service: A Study of Military
Working Dogs Deployed in Operations Desert Shield/Storm )
PRINCIPAL INVESTIGATOR(S): Armed Forces Institute of Pathology (AFIP); DOD
Military Working Dog Veterinary Services (DODMWDVS),; Walter Reed Army Institute
of Research; (listed by Institute because individuals have and will change with the
military)
Agency: DoD Location: AFIP, Washington, DC Status: Ongoing
Contact Name: LTC Robert Moeller Contact Phone : 202-782-2600
Contact Email: moelier@email.afip.osd.mil Contact Fax: 202-782-9150

RESEARCH TOPIC: Outcome RESEARCH SUBTOPIC: Epidemiology

OVERALL PROJECT OBJECTIVE: The possi of exposure to environmental
factors and endemic diseases exist for the population of military working dogs (MWDs)
that deployed to the Persian Gulf (PG) theater of war. The question to be answered is:
in the final analysis, what are the differences in diagnoses between the PG MWD cohort
and a matched (on the basis of age, sex and breed) comparison group which never
deployed to Southwest Asia (SWA).

SPECIFIC AIMS: The (null) hypotheses to be tested is that in the final analysis there
will be no differences in the diagnoses between the PG MWD cohort and the
comparison group which never deployed to SWA. Should this hypothesis not be
supported: 1) the possibility exists that differences in diagnoses between the two
groups may be the result of deployment to SWA; and 2) dates of deployment and
location in theater will be compared among the PG MWDs, and conceivably to those of
PG veterans.

METHODOLOGY:

The PG MWD cohort was identified after the cessation of hostilities and
subsequent redeployment. The inclusive deployment dates for this population are 1
August 1990 to 31 December 1991.


30

Proposals submitted in response to BAAS for the GWVI program undergo a two-tiered,
scientific-peer and programmatic relevance, review process. The review for scientific merit is
conducted by an independent organization; the reviewers are non-DoD personnel who are experts
in the appropriate biomedical disciplines.

The in-depth review for programmatic relevance is conducted by the RWG. This
programmatic review is intended to identify those proposals which best fulfill research needs
including program requirements, avoidance of unnecessary duplication, and are judged to possess
the sound potential for advancing program goals and fulfilling research objectives. Blinded
scientific critiques of each proposal that include summaries of the proposed effort, scientific merit
scores, and detailed assessments of proposal strengths and weaknesses serve as the basis for the
RWG programmatic review. The RWG recommends a slate of proposals for award and also
provides recommendations on any adjustments to statements of work and any associated
modifications to budget requests.

The project officer and contracting staff receive the RWG recommendations and begin
deveiopment of essential information needed for ensuring regulatory compliance. This includes
compliance with the National Environmental Policy Act (NEPA-40 CFR 1500-1508) requirement
for integration of considerations of potential environmental consequences of the proposed action
into the decision-making process. In most instances proposals qualify for a categorical exclusion
and a Record of Environmental Consideration is prepared in accordance with Army Regulation
200-2, Environmental Effects of Army Actions, 23 December 1988 (32 CFR 651). If the
proposed work does not qualify for a categorical exclusion then an environmental assessment is
required. Individual offeror’s certification of environmental safety and compliance must be
included with the proposal (Attachment 1)

If the proposed work requires the study of etiologic agents as part of the biological defense
program, then the provisions of 32 CFR 626 and 32 CFR 627 concerning biological defense
research safety would have to be exercised. These include pre-award site visits and establishment
of special safety provisions to ensure worker and environmental safety. Similarly, work requiring
the use of chemical warfare agents must fulfill special safety and surety requirements depending
on the type and quantity of agent required. Work with either biological defense categories of
etiologic agent or chemical warfare agents necessitates implementation of special contract
provisions and reporting requirements, Facility safety plans (Attachment 2) must be included with
the proposal for work in laboratories that may pose special risks.

Proposed use of human subjects or of animals also requires special review requirements as
well as implementation of special contract clauses and reporting requirements. Protection of
human subjects is defined by 32 CFR 219 and implemented by Department of Defense Directive
3216.2 and in the Army by Army Regulation 70-25. Proposed protocols and informed consent
forms are forwarded to the USAMRMC Human Use Review Officer, who reviews them for
compliance with regulatory requirements and, after resolving any issues, forwards them to The
Surgeon General Human Subjects Research Review Board (HSRRB) for review and approval.
‘Awards based on the general proposal may be made and would carry the prohibition against
proceeding with any research involving human subjects until specific protocol and informed


1

persuasive source. Perhaps most importantly, the superficial
semantics do not attempt to address what the interim rule does
and does not do, and how that relates to the legal and ethical
standards applicable to research and treatment. The rule does
not authorize a determination that informed consent is not
feasible in connection with any military undertaking that fits
the legal, ethical, or clinical description of "research." The
rule allows such a determination only when, based on the nature
of the disease threat, the evidence of safety and efficacy of the
drug to counteract that disease threat, and the lack of a
satisfactory alternative, "withholding the treatment would be
contrary to the best interests" of the military members.

6. Overall, notwithstanding some problems in carrying out
the designed treatment protocols, the two uses made of the
current rule during the Persian Gulf War support the rule's
continuation.

Essentially, during the Persian Gulf War, DoD and FDA
collaborated to do three significant things. One was to
promulgate the rule authorizing a determination by the
Commissioner that informed consent is not feasible in certain
military combat exigencies. This rule was accepted by the courts
and Congress and remains in effect today. The other two
significant actions were the adoption, using the authority of the
rule, of treatment protocols for the use of two IND products as
medical countermeasures against certain suspected chemical or
biological weapons threats. It is important to restate the facts
with respect to these two actions.

With respect to the adoption of a treatment protocol for
pyridostigmine bromide as a pretreatment antidote to nerve agent
poisoning, the FDA thoroughly reviewed the issue through the
Informed Consent Waiver Review Group (ICWRG), which included
senior officials of the FDA, plus the Director of the Office for
Protection from Research Risks (OPRR), HHS. In recommending
approval of the DoD requested determination, these ICHRG members
made the following findings:*

* Memorandum to the Commissioner of Food and Drugs from
Informed Consent Waiver Review Group, Subject: IND 23,509 -
Pyridostigmine Bromide 30 mg Tablets - Action, January 8, 1991.


199

I think the major Problem from a public health point of view, and
the one that should be focused on, is the problem of prevention.
There is evidence that this sort of illness has occurred after every
major war. The major issues that we have is how to prevent this
from happening in the next deployment, or in the next large de-
ployment. I think the issues are, at least as far as issue research,
are issues of case definition; what in fact are we dealing with? We
are dealing with an illness that is very hard to characterize by
physical findings or laboratory markers.

I would disagree very strenuously with Dr. Haley that we have
any markers that will diagnose this illness. So I think a case defi-
nition, I think a search for markers of which there is a variety of
serious research, including Dr. Haley’s, and I think a search for
risk factors that can be intervened are what need to be done, and
I think that looking at the natural history, what is in fact getting
better. We have that problem with chronic fatigue syndrome, where
people are ill for many years and there is fluctuation in symptoms.

fe need an end point against which to gauge our interventions.
But I think the primary questions are questions of prevention and
questions of treatment, probably prevention being the most impor-
tant for the future.

Mr. Suays. We all want to properly diagnose and we all want to
effectively treat and I would think properly compensate our veter-
ans who are sick. But you would all agree or disagree with the fol-
lowing: that some of our Gulf war veterans have come home sick
due to their experience in the Gulf war. Would you agree with that
or disagree?

Dr. REEVES. I would agree with that. I think the difficulty that
I have with that personally is it is very clear in our studies and
those of others that Gulf war illness or Gulf war experience has
precipitated an illness or a variety of illnesses of veterans. But if
I could enlarge, I think the interesting thing in our study is that
15 percent, if one uses the overall case definition that we derive,
of people who did not go to the Gulf war and are in the military,
have a similar illness. Chronic fatigue syndrome is a similar illness
which is experienced by a proportion of the civilian population. So
I don’t think we have seen an illness unique to the Gulf war. I
think we are seeing something——

Mr. Suays. I would like to pursue that, because I am not aware
of a lot of our military men who have described throwing up and
rashes and other things similar to that. They have described cer-
tain other parallels.

Let me just pursue this one question. You can come back and
comment, but not at this moment.

Doctor Clauw, do you believe that our soldiers have come back
sick due to their experience in the Gulf war?

Dr. CLauw. Yes.

Dr. HALgy. Oh, definitely.

Ms. HEIVILIN. Yes. Can I add, since we have soldiers and sailors
over there right now, and airmen, I think it is very, very important
that we pursue the causes so that those that go over there in the
future or stay over there now and into the future, will have some
sense of security that they are not going to have to suffer the same


expand the circumstances in which the Commissioner may
determine that obtaining informed consent is not feasible.

Consistent with this policy, the current rule is an
extremely limited authority. First, it does not waive informed
consent for the military, nor allow the military to do so. It
does not even indicate that the Commissioner of Food and Drugs is
inclined to find that informed consent is not feasible in
military combat situations. It stands only for the proposition
that it might be necessary under certain extraordinary
circumstances to exercise the statutory authority to find that
informed consent is not feasible because of military combat
exigencies.

Secondiy, quoting from the regulation (21 CFR §
$0.23 (d) (1)):

(DoD's] request must also include a written justification
supporting the conclusions of the physician(s) responsible
for the medical care of the military personnel involved and
the investigator(s) identified in the IND that a military
combat exigency exists because of special military combat
(actual or threatened) circumstances in which, in order to
facilitate accomplishment of the military mission,
preservation of the health of the individual and the safety
of other personnel require that a particular treatment be
provided to a specified group of military personnel, without
regard to what might be any individual's personal preference
for no treatment or for some alternative treatment.

Third, a duly constituted Institutional Review Board must
have reviewed and approved the use of the investigational drug
without informed consent. Id.

Fourth, the Commissioner must specifically find that "there
is no available satisfactory alternative therapy." Id.

Fifth, the rule requires consideration of the “extent and
strength of the evidence of the safety and effectiveness of the
investigational drug for the intended use." § 50.23(d) (2) (i).

Sixth, the context in which the drug will be administered
must be considered. § 50.23(d)(2) (ii). A context involving one-


12

detail in the Annual Report to Congress on Federally Sponsored Research on Persian Gulf
Veterans’ Illnesses for 1996 released in the Spring of last year.

Subsequently, DoD published a four-part broad agency announcement (BAA) to
amplify research on low-level chemical warfare nerve agent effects, as well as research on
the health effects of other exposures including insecticides, the nerve agent prophylaxis
pyridostigmine bromide (PB), and stress. The BAA resulted in funding recommendations
for 12 new projects, valued at approximately $12 million, and covering such exposures as
sarin, PB, insecticides, psychological stress, and heat stress, alone and in various
combinations. Additional projects have been recommended for funding. DoD will
announce these new projects at the time of final award.

As part of the BAA the scientific community was asked for proposals for a
feasibility study on the conduct of epidemiological research on the possible health
‘outcomes among troops potentially exposed to sarin at Khamisiyah, Iraq in March 1991.
Unfortunately, there was no response to this request. The Department of Defense asked
the Medical Follow-Up Agency (MFUA) of the Institute of Medicine (IOM) to develop a
protocol for conducting such a study. MFUA designed a protocol that was peer-reviewed
by a panel of experts assembled by the American Institute of Biological Sciences. The
peer-review panel provided a scientifically meritorious score and the RWG recommended
to DoD that this project be funded.

Inearly 1997 VA and DoD tasked the Medical Follow-up Agency of the Institute
of Medicine to undertake feasibility studies on the long-term health effects of exposure to
chemical warfare nerve agents. This work is focusing on MFUA’s access to cohorts of

veterans exposed at Aberdeen Proving Ground as a part of their research on the health


205

search Triangle Institute actually doing the work, so it is independ-
ent from us, to see whether the syndromes we described can really
be found in other groups.

I fully expect, Congressman, that this will not be rated highly by
the peer review groups because it is flying in the face of stress and
the accepted view, and it is also too much money. I think they will
turn us down, in which case we will seek funding in the private
sector as we have done before. But I know what to do with that
blank check. It is all on paper already.

Mr. SANDERS. Do you have any thoughts, Dr. Clauw, or Dr.
Reeves?

Dr. REEVES. Not talking about exact amounts of blank checks, I
think that again, the type of work that is needed does not nec-
essarily cost as much as everybody thinks. My own plan, or our
plans at CDC that have been looking at this illness within the con-
text of Gulf war, are that we are looking very carefully, with the
people at the Center for Environmental Health, Dr. Barrett, who
has the—we are trying to work with as many groups of investiga-
tors as possible to come to grips with a definition of illness. There
are a variety of people looking at ways to analyze this, and in
working with groups who are working independently, one can come
up with case definitions and a case definition, as has been men-
tioned, is critical.

Mr. SANDERS. What about treatment?

Dr. REEVES. Before I would go to treatment, because that is not
really in my purview, I am more interested, as I mentioned earlier,
in preventing this, in looking for markers. In other words, I need
to define an illness that I can treat. Again, in chronic fatigue syn-
drome and in collaboration with funding for people doing Gulf war
research, we are looking at markers in an open-ended fashion, look-
ing at molecular epidemiologic markers, again by pulling things to-
gether and using things from existing studies. One does not nec-
essarily need a huge amount of extra resources. I think the treat-
ment issues and again the prevention issues are dependent on a
case definition and on some knowledge of the etiology.

Mr. SANDERS. Thank you. Anyone else want to comment on that?

Dr. CLauw. I would just agree with what both people just said.
I think that we are all talking about the same type of thing, and
that in addition to what the Government is already doing, these
types of institutes that would be able to do cross-cutting, multi-
disciplinary research will be helpful to look at these kinds of prob-
lems. I think that is what Dr. Haley was describing. That is cer-
tainly what I was describing earlier.

Again, I would say that it needs to be in addition to, not instead
of, what the Government is doing. I looked at the list of projects
that have been funded and I had a hard time finding any of them
that I didn’t think would lead to useful information or helping us
really understand this problem. It is a huge problem, and it seems
like there is a lot of money being spent on it, but given the mag-
nitude of the problem, it is not that much.

Ms. HEIVILIN. Can I respond?

Mr. SANDERS. Yes.


54

‘The Research Working Group also serves as a forum for research data exchange among
the three departments and among federally funded investigators. This includes the maintenance
of a research database on all VA, DoD, and HHS research activities. VA, DoD, and HHS share

in the responsi

for tracking research projects and updating the research database, which is
maintained at the VA Office of Research and Development. The Research Working Group also
‘sponsors an annual investigators meeting where new research results are shared. HHS
participates on the planning subcommittee for this effort.
CDC Gulf War Research Activities:

Now I would like to review CDC’s research activities relating to Gulf War veterans, with
a special focus on our current activities and how these activities were selected and funded. Our
involvement in this research effort began not long after the cessation of hostilities when in May
1991 researchers from NCEH and several other Federal agencies conducted cross-sectional
surveys of workers in Kuwait City and of firefighters in the oil fields in October 1991. Since this

ial research effort, CDC has continued to contribute to our understanding of the health effects
of military service in the Gulf War through a variety of studies. Besides studies on the health
effects of exposure to oil well fire smoke, CDC researchers have conducted studies addressing
the prevalence of birth defects among Gulf War veterans, and have completed two large
epidemiologic studies documenting the prevalence of symptoms and conditions among Gulf War
veterans in comparison to Gulf War era controls, the Iowa and Pennsylvania Air National Guard
studies.

ur involvement in the Gulf War research effort has been initiated through a variety of

mechanisms. For example, the fowa study was conducted in response to a Congressional request


171

has been known as “the Sanford definition.” It was written down,
it was disseminated, and then something happened; we don’t know
what happened, but at that point, just as it was about to be used,
the CCEP was inaugurated and we went off in the other direction
of examining tens of thousands of Gulf war veterans with standard
medical examinations that had no chance of finding neurotoxicity,
OK? That, I think, took all of the interest and strength and money
away from epidemic investigations.

At about that time, I think a far-reaching policy was established.
I think that policy was that there is no single epidemic disease.
That was based on no data, but that was decided. Second, that sol-
diers’ symptoms are due to posttraumatic stress disorder. Third,
that large epidemiologic studies, big statistical studies, should be
done to show that this is really not hurting anybody; and fourth
a public relations campaign should be waged to convince the Amer-
ican people and the scientific community that this is not really a
problem. In other words, I believe it was decided in early 1994,
that this is not a problem and we are going to make sure that it
doesn’t get mistaken to be one.

Accordingly—now this is very important. Accordingly, orders
went down through the DOD and the VA medical authorities that
a doctor may not write down the diagnosis of “Gulf war syndrome”;
that may not be recorded in a medical record. If you look in the
medical records, it is never recorded. I have talked to many medi-
cal people in the DOD and the VA who say, “Oh, well, you know,
we cannot write that down. That is not allowed.”

So this became the policy. I believe that what happened after
that was a pervasive exercise in what I call “conservation of belief.”
That is, all incoming information that would challenge this belief,
this policy, was unconsciously filtered out, and I think by well-
meaning people. All studies were designed to confirm the lack of
physical effects, again, by well-meaning people who probably didn’t
realize that that is what was happening, and research delving di-
rectly into hypotheses of environmental causes was discouraged
subtly by lack of funding, and by excessive criticism that would
never have been leveled at epidemiologic studies of epidemics from
CDC back in the past.

Now, this had a number of systemic effects. Let me list some of
them in whatever time that we want to go over this. First, since
no case definition of Gulf war syndrome was sanctioned and, in
fact, doctors were forbidden to write it down in an individual pa-
tient’s records, the CCEP and the VA registries found only all of
those other things that veterans might have in addition to their
Gulf war syndrome—you know, their stomach ulcer, their lung dis-
ease, whatever, and they found no Gulf war syndrome. Why? Be-
cause they were forbidden to write it down. This led to the ubiq-
uitous expression that we hear all the time: “There is no single dis-
ease, only a variety of symptoms.” That is a self-fulfilling prophecy,
and a reaffirmation of the policy.

Second, 16 different studies were done to look for posttraumatic
stress disorder. Most of them used a psychometric screening device
called the Mississippi PTSD scale or other similar instruments.
These are not diagnostic. When they are positive, there is a very
high probability that they are false positive, OK?


STATEMENT BY
EDMUND G. HOWE, M.D., J.D.
PROFESSOR OF PSYCHIATRY; DIRECTOR OF PROGRAMS IN MEDICAL ETHICS

(UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES)

BEFORE THE
PRESIDENTIAL ADVISORY COMMITTEE
ON GULF WAR VETERANS’ ILLNESSES

USE OF INVESTIGATIONAL DRUGS AND VACCINES IN THE GULF WAR

ETHICAL CONSIDERATIONS IN WAIVING INFORMED CONSENT
FOR MILITARY EXIGENCIES

JANUARY 12, 1996

NOT FOR PUBLICATION

UNTIL RELEASED BY

PRESIDENTIAL ADVISORY COMMITTEE
ON GULF WAR VETERANS‘ ILLNESSES


185

has transpired with respect to the cause(s) of Gulf War illnesses. There appears to be
a wide chiasm between two seemingly disparate views: those on one hand who fee!
that these illnesses were triggered by “stress,” and others who feel that toxins or
infectious agents were involved. The scientific reality is that toxins and infectious
agents can act as biological “stressors,” in much the same way as physical trauma,
drugs, and emotional stress. Just as there are many different types of “stressors”
which appear to be capable of triggering or worsening Fibromyalgia, Chronic Fatigue
Syndrome, and Multiple Chemical Sensitivity, there are likely to be a plethora of

exposures which may have contributed to the development of Gulf War illnesses.

I give this background because the governmental effort to research the causes
and treatment of Gulf War illnesses must be judged in the context of the complexity of
the problem. These ilinesses are difficult to define and diagnose, have been poorly
studied to date, and are likely to be caused by complex interactions between an

individual and numerous types of stressors.

With this in mind, my opinion is that the government research agencies in
general, and the Research Working Group of the Persian Gulf Veterans Coordinating
Board in particular, have performed very credibly. My sense is that each government
agency has examined their strengths and weaknesses in these areas, and has
promoted internal research in areas of strength, and looked toward outside expertise

and external funding in areas of weakness. This is a logical approach. For example, it


170

ot pHAYS. Thank you very much. I think we are now going to
r. Haley.

Dr. HALEY. I am poing to talk today as a private researcher out
in the private world who has been working on this full-time for 4
years, but pretty much outside the Government realm, outside of
the decisionmaking process, which gives me the advantage of not
having been involved in the decisionmaking and influenced by it.
On the other hand, I don’t know how the decisions were made.

My overall impression of the Government’s research effort,
though I think well meant, particularly recently, and painstakingly
thought out more recently, has really misfired and is showing little
sign of getting back on track in a way that is really going to solve
the problem, which I think is your concern. Here is why.

First of all, a little history. I think as our troops returned from
the Gulf, it appears now in retrospect that about 10 to 20 percent
of the 700,000 may have been affected by an epidemic disease. That
is, there really may be a real disease. In anybody’s book, that
should have triggered an epidemic investigation. Now, that is not
an epidemiologic study, in a broad sense, the types of studies that
we have been seeing. There is a very carefully worked out “fire
drill,” you might say, that the CDC has been using for 30 years to
investigate epidemics, and that has not been applied, except in one
instance. Now, what is that?

Actually, it almost happened. Back in 1991, late 1991 and early
1992, the Navy epidemiology group in San Diego sent out teams
and started looking at some of the affected units and performed ini-
tial descriptive epidemiology, and they came up with symptoms
that might be a syndrome. What they didn’t do, though, is write
down a case definition, as my GAO colleagues have emphasized.
That should have been the first step, and then we should have
done a case-control study dividing people, possible exposed groups,
into the cases meeting the case definition and controls, not meeting
the case definition and we should have identified risk factors. This
sounds theoretical, but this is the way it has been done for 30
years: Identify risk factors by doing careful questionnaires of self-
reported exposures in the war, like being in the area where chemi-

alarms went off and so forth. Then, do analyses to see which
of those risk factors are associated with being a case and not with
being a control. In other words, they are significantly related with
the cases.

Now, that is not definitive, but then you go a step further, and
any risk factors that are positively associated like that, you then
introduce those into animals in experiments, and if you get a posi-
tive—you reproduce the disease that you see in the people—then
that is very strong evidence. That is the model that was used to
solve hundreds and hundreds of epidemics over the last 30 years,
such as Legionnaire’s disease, toxic shock syndrome, AIDS, and on
and on and on. This was not done for the Gulf war syndrome. This
is the standard technique and it was not applied.

It almost was, though. Back in 1993, Dr. Ronald Blanck who was
at Walter Reed, who is now the Army Surgeon General, was on
that track and he commissioned Dr. Jay Sanford, who is one of the
greatest military medical experts of this half of the century, also
a good epidemiologist, had him formulate a case definition which


“iy

rescue agent would need to be available, in case the protective agent failed and a
potentially fatal toxicity had to be reversed. Antidotes to probable threat agents do not
currently exist.

Issue C: If products that may be used to provide potential protection against toxic
chemical and biological agents cannot be ethically tested in humans, what evidence
would be needed to demonstrate their safety and effectiveness?

C(I). Should FDA identify the evidence needed to demonstrate safety and
effectiveness for drugs that cannot ethically be tested on humans to demonstrate
efficacy when such tests would involve administering a severely toxic substance to
human volunteers? If yes, what should constitute the evidence needed to demonstrate

safety and efficacy?

Safety and efficacy data from well-controlled animal studies can serve as the
basis for approval of certain drugs or biologics for humans. Four requirement
categories for generating safety and efficacy data are provided.

1. Animal studies should clearly show efficacy. A validated animal
model should be selected which has biological and mechanistic relevance to
humans for the toxicology of the compound and the pharmacology of the
antidote.

2. Animal studies should show a functional relationship between a surrogate
marker and efficacy. A change in the surrogate marker should reflect a change
in efficacy.

3. The surrogate marker needs to reflect the pathophysiology of the toxic
process.

4. The surrogate marker should be measurable in humans. The drug or
biologic agents should produce in humans the surrogate endpoint that would
indicate detoxification of the chemical or biological weapon. The kinetics
and/or pharmacodynamics of the drug or vaccine should be sufficiently
understood to allow estimation of an effective dosing regimen in humans.

In addition, other information should be obtained in order to better understand and
perhaps predict the reactions of the drug or vaccine when given to a large group of
DoD personnel. These might include metabolic and disposition pathways in both the
animal model and in humans and population studies in humans to understand clinical
covariates to predict response ranges in very large groups.

C(2) If the agency were to identify the evidence needed to demonstrate safety
and effectiveness of these products, would this preclude the need for the interim rule?
What specific advantages would this offer over the interim rule?


36

ATTACHMENT 1
(CERTIFICATE OF ENVIRONMENTAL COMPLIANCE’

CERTIFICATE OF ENVIRONMENTAL COMPLIANCE

The offeror currently ___IS_IS NOT in compliance with applicable national, state, and local
environmental laws an regulations. //f not in compliance, attach details and evidence of approved
mitigation measures.]

The offeror has examined the activities encompassed within the proposed action entitled "" fenter
title and/or Solicitation number and Principal Investigator's name], for compliance with
environmental laws and regulations. The offeror states that the conduct of the proposed action
__ WILL ___ WILL NOT violate any applicable national, state, or local environmental law or
Tegulation. [Ifa violation will result, attach details describing the nature of the violation and
evidence of approved mitigation measures.]

The offeror agrees that if the work required under the proposed action at any time results ina
violation of any applicable environmental law or regulation, the offeror will immediately take
appropriate action, to include notifying the Contracting Officer, and coordinating with the
aporopriate regulatory agencies.

(Name of Official Responsible for Environmental Compliance)

Signature

(Title)

Date

(Name of Organization)

USAMRMC FORM 65-R
1 Oct 94

' From U.S. Army Medical Research and Materiel Command Broad Agency Announcement 95-1


181

trial for persons with these conditions. This project is undoubtedly
the largest single clinical trial that has ever been performed in this
type of illness and, in fact, the amount of money that has been set
aside for this effort by the VA probably exceeds the amount spent
on all treatment trials ever performed on these types of illnesses.

I was also asked to specifically comment on the procedures to re-
view and fund research proposals. Although I do not know the pre-
cise mechanisms which have been used, the peer reviews of my two
grants were every bit as critical and stringent as for NIH grants
which I have submitted. In fact, the DOD even took the unusual
step of asking the internal principal investigators to modify their
proposals in response to the peer review comments, an extra step
which is more stringent than the post-review process for funded
NIH or National Science Foundation grants.

Although I feel that the Federal research effort to date has been
appropriate, I have several comments suggesting future direction of
these endeavors. First, we must acknowledge that it is likely that
we will never know precisely what caused Gulf war illness. It has
become clear, and numerous people have pointed out today, that
there was inadequate information collected on veterans’ prede-
ployment health and on their potential exposures and stressors to
learn precisely what made certain ple ill. But we still have
ample opportunities to learn about the cause of these conditions.
Nearly all of the environmental exposures suspected to cause Gulf
war illnesses also occur in the general population. And we know
that some individuals exposed to physical trauma, emotional stress,
infections, drugs, toxins and other types of stressors develop these
chronic nonspecific symptom complexes, whereas many others do
not. These individuals and the illnesses they develop need to be
more extensively studied.

But even if we don’t know exactly what caused the illnesses,
again it has been stated that we need to get on with treatment of
these conditions. Most who have studied these syndromes have
agreed that although there may be many different types of triggers
of these illnesses, once someone develops these conditions, the
treatments are very similar. My opinion is that we have all been
collectively paralyzed by this need to know what caused Gulf war
illnesses and that we must aggressively move forward in pursuing
treatment programs.

Last, I feel that research into the causes and treatments of these
conditions may require some additional strategies to augment those
employed to date. Much of the currently funded research has been
on individual projects proposed by individual investigators who are
pursuing their scientific hypotheses. These investigator-initiated
projects have the advantage of promoting innovative ideas, but
there are also significant disadvantages to this approach, including
the fact that there is concurrent funding of duplicative efforts and
there is very little coordination between projects. In most complex
medical conditions such as cancer and AIDS, we have realized that
there is a need for a more integrated approach which can link pop-
ulation-based epidemiologic studies, physiologic studies and treat-
ment protocols, I feel that a similar strategy, modeled after the “in-
stitutes” that have been formed to comprehensively study other ill-
nesses such as cancer, would be helpful in studying post-deploy-


48

ATTACHMENT 4
RESEARCH INVOLVING ANIMALS‘

Each of the items listed below must be addressed in a proposal appendix entitled "Research
Involving Animals." If an item has been fully covered in the proposal, reference the page number
and section. Questions concerning animal use should be directed to the USAMRMC Animal Use
Review Office, in care of Commander, U.S. Army Medical Research and Materiel Command,
ATTN: MCMR-RCQ, Fort Detrick, Frederick, MD 21702-5012, Telephone (301) 619-2144.

1. Alternatives Search: Identify the services (computer databases, literature searches, etc.) that
were used to obtain inform: on alternatives to painful procedures and to the use of live
animals, It is USAMRMC policy that alternatives to the use of animal models be thoroughly
investigated prior to submission of any protocol involving animals. The USAMRMC reserves the
right to request evidence that a search for alternatives was

performed.

2. Species Identification: Identify the species of animal to be used and the estimated number of
each species to be used in the proposed study.

3. Rationale: Provide a statement of the rationale for using animals, for the species proposed, and
for the number of animals to be used in the proposed study.

4, Animal Use: Provide a complete description of the proposed use of animals. Describe what
anesthetics, tranquilizers and analgesics will be used. If none, why?

5. Euthanasia: Describe the euthanasia methodology. Approved methods are listed in the "1993.
Report of the American Veterinary Medical Association Panel on Euthanasia.” If animals are not
euthanized, state final disposition of the animals.

6. Accreditation: Provide one of the following:

a, Evidence that the contractor's facility is accredited by the Association for the
Assessment and Accreditation of Laboratory Animal Care (AAALAC).

b. A copy of the contractor's Institutional Letter of Assurance of Compliance with the
Public Health Service Policy on Humane Care and Use of Laboratory Animals, revised
September 1986.

¢. A statement signed by an official of the contractor's Animal Care and Use Committee
that the care and use of animals will be done according to NIH 86-23, 1985 Edition,

“Guide for the Care and Use of Laboratory Animals,” or other applicable Federal permits
and regulations.

“From U.S. Army Medical Research and Materiel Command Broad Agency Announcement 95-1

a1


7

Some of the newer discoveries that the research has produced
you are aware of. For example, the PB story, when stressful situa-
tions are overlaid on the administration of that drug, the blood-
brain barrier may be modified so that the drug can get across.

The Japanese have made observations that there are brain ab-
normalities noticed that persist long after the acute exposure,
months after the acute exposure. Those abnormalities may not be
explainable on the basis that the nerve agent blocks acetyl cholin-
esterase. There may be other actions of that chemical.

The methodological issues and the causation issues are problem-
atic, and you know that.

I feel that if we had some definitive treatments, we would be-
come less concerned about cause because at least we could do some-
thing better for the patients. I actually did not see Frontline per-
sonally, but I do not believe that all of these various complaints fit
neatly under one diagnosis of stress. I think that much of the re-
search has shown that this is more complicated than that.

So I would be reluctant to blame stress as an explanation for all
of this, on the one hand.

On the other hand, our patients think of stress or stress-related
diseases as mental illnesses; they are diseases of the brain and the
brain is a physical entity. Some of our research on the neurobiology
of stress, the neuroendocrinology of stress, the effect of stress hor-
mones on the immune system, provide mechanisms for more tradi-
tional disease situations to arise.

You asked about treatments. Now, we don’t have definitive treat-
ment protocols. What the Department has done is tried to treat pa-
tients symptomatically. I think that we have been fussing over try-
ing to come up with a case definition so we can study Persian Gulf
veterans’ illness, and we can’t come up with a case definition so we
don’t generate treatment protocols.

What we have done recently, in part in response to this commit-
tee’s criticism, is to try to take parts of the larger problem,
fibromyalgia, chronic fatigue syndrome, for example, and craft
treatment trials for those conditions. We are in the midst of plan-
ning a trial that involves cognitive behavioral therapy and exercise
therapy for chronic fatigue and fibromyalgia respectively.

Dr. Nicholson proposes a hypothesis that this condition—at least
part of the Persian Gulf veterans’ illness—is related to infections
with an unusual mycoplasma organism. I think that is a tractable
problem, and I think that Dr. Nicholson has been working with

‘alter Reed and investigators there, and at our last meeting we
discussed the Possibilities that we could actually plan an antibiotic
treatment trial.

Mr. SANDERS. Let me, with your permission, Mr. Chairman, and
for the record—you see, this is the problem that we have. This is
a letter—I spoke to Dr. Nicholson. Phappened to be in California
last week. This is to Congressman Filner of California.

i i ith you and Ci ssman Sanders on Sunday,
Februsey ith, i Ghula Vista, Wo were disturbed tarigd out that the Veterans Ad
ministration indicated to your committee that we are fully funded by the DOD for
our work on identifying mycoplasmal infections of Gulf war illness patients. This is
not true, We do have a pending contract with the U.S. Army Medical Research and

Acquisition Command at Fort Detrick, but this has not yet been approved or funded.
‘We did receive some small funds, $40,900, from the U.S. Army to train DOD person-


53

research direction. When the input of experts on a specialized research topic is needed, HHS
scientists who are not regular members of the Research Working Group have provided
consultation on specific projects and have participated on special subcommittees managed by the
Research Working Group. Examples of this include the involvement of a CDC scientist with
particular expertise in chemical warfare agents on a subcommittee addressing low level nerve
agent exposure health effects, involvement of CDC, NIH, and Food and Drug Administration
scientists with expertise in parasitic diseases on a subcommittee regarding serological testing for
detection of leishmania infection, and consultation of CDC and NIH infectious diseases experts
‘on mycoplasma infection issues. NIOSH and ATSDR have also been involved in providing
consultation to the Persian Gulf Veterans Coordinating Board on health risk communication
issues.

Through participation on the Subcommittee for Project Funding Recommendations, HHS
has provided input into the programmatic review and funding recommendations of the Research
Working Group. Specifically, this has involved a process where DoD, VA, and HHS
representatives review abstracts of peer-reviewed proposals along with written reviews of the
peer-reviewers and their scientific merit scores. The submitting investigator's names and
institutions are removed form these abstracts and peer reviews in order to minimize any potential
bias. The Subcommittee is charged with reviewing this information in order to rate the proposals
for relevance to the programmatic needs as outlined in the Research Working Plan, This process
was used to rate the relevance of proposals submitted in response to recent DoD Broad Area
Announcements and to a CDC program announcement. Only proposals that receive scientifically

meritorious ratings through the peer review process are recommended for funding.


204

clinical trials and we would be very happy to provide you a copy
of this report which articulates this methodology.

Mr. SANDERS, One last question, Mr. Chairman, a brief one, and
it was thought of with Dr. Haley and we can go elsewhere, Dr.
Reeves, Dr. Clauw—if we gave you the blank check and we said—
and picking up the point that the chairman made an hour ago that
there does not seem to be that sense of urgency, he and I believe
that there is a sense of urgency. We want to see this problem re-
solved as quickly as possible, not discussed 20 years from now. If
we gave you the resources and appreciated your sense of urgency,
what would you do?

Dr. HALEY. Well, last March I submitted a grant proposal which
was developed by about 30 members of our faculty, which is not an
inconsequential medical school. We developed a plan that in 3

ears would develo; anted, there is no test right now that any-

jody would consider definitive, including myself, but we proposed
to develop such by testing all known me lologies that would look
at subcortical brain function and brain stem function and so forth,
which we think is the problem. It would also come up with a treat-
ment by doing several sequential trials in very careful ups of
studies. We would combine it in parallel with animal studies, test-
ing the same thing in animals so we could correlate this and so
forth. It was a very complicated thing and the price tag on it was
$16 million; $16 million, including indirect costs.

Mr. SANDERS. $16 million.

Dr. HALEY. $12 million direct cost and the rest overhead. We pro-
posed that. It went through the peer review process. The peer re-
viewers raved, thought the comments—and I will show you the
comments privately if you want, I don’t want to show them to the
media who wants them—but the peer review comments of our work
to find a test and to do the treatment component were very, very
positive. They really didn’t like the animal and the basic chemistry
studies on PB that we are doing. I think they misunderstood them.
They don’t like them. As a result, we got only a moderately good
summary score. The Persian Gulf Veterans Coordinating Board
looked at it, and no funding. The Defense Department then real-
ized what had happened, came back to us and decided to give par-
tial funding for the human studies. The leadership of the Presi-
dential Advisory Committee went ballistic, along with some of the
members of the Persian Gulf Veterans Coordinating Board, went to
the Washington Post and smeared us, and some of the Defense De-
partment authors of scientific studies are putting similar comments
in the medical press.

You see, the problem is, if you step out and you really want to
go against the policy, which I mentioned a while ago, you are going
to get fried, and that is why nobody in the Defense Department or
the VA or the CDC is going to do it, because they all realize they
are going to get fried if they do it. Everybody will deny that, but
look what happened to us. We ended up getting $3 million from the
Defense Department with the invitation to come back and put our
protocol, the second part that is going to cover 6 months worth of
work, and we are about halfway into that now. We just put in an-
other—two more grant proposa to cover the second 6 months and
to cover a big survey. We are proposing to do a survey with Re-


138

Ms. WINEGAR. If the question were open-ended for any chemical,
then I would agree with Dr. Feussner that yes, that definitely is
a ibility.

ir. SHAYS. Well, he didn’t really $9) el

Ms. WINEGAR. Maybe I am going a little bit further.

Mr. Suays. Dr. Newton came to the rescue of all of you, I think,
by saying that some chemicals could lead to chronic illness and
death, which is a basic statement that you don’t need to be a Ph.D.
to know.

Ms. WineEGar. Right. But that leads me back to the answer that
I wanted to give to your current question on——

Mr. SHays. Well, before we do that, I want to know under what
context would you have answered differently? I don’t understand
why you gave your first answer, regardless of —

Ms. WINEGAR. Oh, my answer was limited to chemical warfare
agents, and I don’t think we have enough data on low-level expo-
sure to such things as sarin, et cetera, to indicate whether that
could lead to serious illness or death.

Mr. SHays. Well, we made an assumption in DOD that because
people didn’t die on the spot, therefore our troops weren’t exposed
to chemicals. That was one of the things that set our hearings off.
There was an assumption on the part of DOD that because there
was no chronic illness and death, therefore our troops were not ex-
posed to chemicals. Case closed.

Ms. Winecar. I think you mean acute.

Mr. Suays. What?

Ms. WINEGAR. There was no acute illness or death; therefore, the
assumption was that there was no exposure.

Mr. Suays. Yes, that’s exactly what I mean.

Ms. Winecar. And I think that we have insufficient data to
make that conclusion at the moment.

Mr. Suays. And I think it is an outrage that that statement guid-
ed our research for 3 years into not looking at low-level chemical
exposure.

's. WINEGAR. I would like to indicate that we do currently have
a number of studies ongoing, looking at exactly that point.

Mr. Suays. Right. It is amazing to me that we haven’t been look-
ing at this for years; I mean after World War I, I would think. See,
we had troops who had acute illness and became sick and died. Ei-
ther they died on the spot or they died quickly after coming home
from World War I. We also had troops who had low-level exposures
to these and died later on. They didn’t die right away, but they
died later on. And for me, in my wildest imaginations, I can’t com-
prehend that DOD wouldn’t have been researching this for years.

Then what really bothered me was that we had Dr. Joseph and
others say we hadn’t done any research on chemical exposure, and
then we find out that you have a long list of studies that were done
on chemical exposure in past years, you just didn’t bring them out.
And you didn’t bring them out, in my judgment, because our troops
weren't exposed to chemicals. And then at 12 o’clock, DOD an-
nounces that at 4 o'clock they are going to have a press conference,
before a Monday story by Jack Anderson and our hearings on Tues-
day, that our troops were exposed to chemicals in Khamisiyah, and
then all of a sudden we have a different attitude.


49

7. IACUC Approval: Provide evidence that the protocol was reviewed and approved by the
principal investigator's Institutional Anima! Care and Use Committee (IACUC). If it was not
possible to have the protocol reviewed by the Committee prior to submission of the proposal,
then so state. Evidence of Committee review can follow but must be provided prior to award.
RESEARCH WILL NOT BE FUNDED WITHOUT EVIDENCE OF APPROVAL OF THE
ANIMAL CARE AND USE COMMITTEE.

8. USDA Inspection Report: Include a copy of the most recent U.S. Department of Agriculture's
APHIS Form 7008, Inspection of Animal Facilities, Sites or Premises.

9 Assurances: Provide a signed statement from the principal investigator for the following:

4. L assure that discomfort, pain, and injury to animals will be limited to that which is
unavoidable in the conduct of scientifically valuable research, and that analgesic, anesthetic
and tranquilizing drugs will be used where indicated and appropriate to minimize
discomfort and pain to animals.

b. Lassure that the animals authorized for use in this protocol will be used only in the
activities, the manner, and quantities described herein, unless a deviation is specifically
approved by my IACUC and the USAMRMC Animal Use Review Office.

¢. Laccept full responsibility for the proper care and use of the animals during the conduct
of research outlined in the proposal.

d. I verify that I have made a reasonably good faith effort to ensure that this protocol is
not an unnecessary duplication of previous experiments. (The USAMRMC reserves the
right to ask for evidence that a thorough literature search was performed.)

. I verify that the personnel performing the animal procedures/manipulations described in
this protocol are technically competent in those procedures, and have received their
training on the use of animals in research, as required by the Animal Welfare Act of 1985.

For proposals which require the use of non-human primates, companion animals, marine
mammals, or protocols deemed sensitive by USAMRMC, a site visit shall be conducted as
necessary by the Contracting Officer and the USAMRMC Animal Use Review Officer, or
designees.

42


18

continuation. It was used only twice, both times for well
established drugs about which very strong evidence of safety and
efficacy was documented. It was never used for exotic or
"experimental" drugs. Finally, DoD initiatives since the Gulf
War, including those taken for Operation Joint Endeavor in
Bosnia, have improved our ability to implement medical
countermeasures under the authority of the current rule, should
that become necessary in the future.

It has been nearly six years since the current rule was
approved by the Secretary of Health and Human Services in
anticipation of imminent hostilities in the Persian Gulf War.

The rule was accepted by the courts, by Congress, by the press,
and by the public. Remaining dissenters are few, and are
unencumbered by any responsibility for the lives and safety of
the personnel sent by the President into military operations.
Even with critical hindsight, the interim final rule stands today
as a scrupulously limited, well justified authority. DoD remains
quite interested in working with the FDA on possible refinements
to the rule and improvements in implementation procedures, as
well as on methods to expedite approval of appropriate drugs and
vaccines needed for military operations.

We cannot predict the next occasion on which the President
will determine that the national interest requires the deployment
of U.S. military personnel, nor the exact threats they will face.
We can, however, predict that the best medical countermeasures
may well include the treatment use of an investigational new
drug. And we can be certain of our duty to provide the best
medical countermeasures available. For these reasons, the
Department of Defense believes it is a national defense
requirement that the authority of the current rule be maintained.

We urge that the petition be denied.

Sincerely,

Aun &

Stephen C. Jésegh, M.D., M.P.H.

Attachment


10

FDA's Accelerated Approval regulation, 21 CFR § 314.500, et seq.
Under that regulation, an IND can be approved for marketing, and
thus widespread treatment-use, even if there is "uncertainty" as
to clinical benefit, contingent on further post-marketing studies
to follow. § 314.510. Post-marketing restrictions on
distribution, labeling, and advertising may also be imposed
pending additional evidence of safety and efficacy. §§ 314.520,
314.550, 314.560. However, during this process of conducting
additional studies and collecting additional evidence, general
uses of the drug are not considered to be research, nor are they
subject to the protection of human subjects regulations.
Additionally, FDA regulations also allow "treatment uses" of
INDs, separate from ongoing research trials. 21 CFR § 312.34.

Once it is recognized that the use in a military combat
exigency of drugs not yet approved by the FDA for general
commercial marketing for the particular clinical indication is
not “research” under law or ethical standards, the ethical
justification for the mandatory use of protective drugs is not
seriously debatable. Military members must make many sacrifices
that in the civilian world would be considered intolerable. The
Supreme Court has said: "The essence of military services is the
subordination of the desires and interests of the individual to
the needs of the service."? Although military members do not
give up their interest in not being nonconsensual research
subjects, they must subordinate many individual interests to the
needs of the military to complete successfully the mission.
Among these is to accept preventive or therapeutic medical care
that command authorities decide is necessary for the preservation
of the fighting force.

Those who refuse to acknowledge legal and ethical
justifications for the interim final rule rely essentially on a
single semantical argument: that anything categorized by the FDA
as an "investigational new drug" is an "experimental drug," which
cannot be used for anything except “research." But this
semantical argument is not based on any meaningful analysis of
the Food, Drug and Cosmetic Act, FDA regulations, the Common Rule
for the Protection of Human Subjects in Research, the Belmont
Report on which the Common Rule was based, or any other

> Goldman v. Weinberger, 475 U.S: 503, S07 (1986).


43

b. List the name of principal investigator and associate(s), if applicable, conducting the
study.

c. Include a statement that the study involves research and an explanation of the purposes of
the research. In general, the structure of the informed consent form:

(1) Should be readable (written in 8th grade reading level language).

(2) Should contain, when feasible, non-medical language that is easily understood by
the subject. One must take into consideration the age group, reading level, and
education of the prospective subject.

(3) Should be translated if a subject enrolled in a study does not comprehend English
The following statement and additional information must be on the English version of
the consent form "I certify that this is an accurate and true translation." The
translator's signature, typed name, address, phone number and TELEFAX number
should also be included,

(4) Should speak to the research subject in the first person singular "I" and/or second
person "you."

(5) Subjects are to be told, within the consent document, that they will receive a copy
of the consent form. A copy of the consent form must be provided to subjects.

4. Include a statement indicating the expected duration of the subject's participation (e.g.,
the number of hours, days, weeks, months).

€. Provide a description of the procedures to be followed and identify any procedures which
are experimental.

(1) Briefly explain the study design relative to what will be done to the subject (in
blind or double-blind studies, subjects must be informed that they may receive either
the experimental modality or a placebo). Ifa placebo is used, its contents should be
described

(2) Specify what is required of the subject (hospital visits, blood donation, etc). The
amount of blood should be expressed in lay terms, e.g, teaspoonsful.

(3) When experimental procedures, pharmaceuticals, or devices are to be used, an
Investigational New Drug/Investigational Device Exemption (IND/IDE) approval
must be obtained from the FDA. The subject should be advised that the IND/IDE is
permission for the study to be undertaken but does not indicate the FDA approval for
the routine use of the drug or device in the method stated in the protocol or proposal
If'a drug or device covered under an IND or IDE is involved, it must be clearly
indicated in the consent form that it is investigational for the purpose of this research.



129

‘THE DEPARTMENT OF DEFENSE ORGANIZATIONAL STRUCTURE.

Organizational Strcture

Office ofthe Secretary of Defense
Military Departments

“The Joint Chiefs of Staff and Joint Staff
‘Unified Combatant Commands.

‘The Department of Defense (DoD) (DoD Directive $100.1) is responsible for providing the military forces needed to deter
‘war and protect the security ofthe United Siaes. The major elements ofthese frees are the Army, Navy, Air Force, and
Marine Corps. Under the President, who is also Commander-in- Chie, the Secretary of Defense exercises authority, direction,
‘and contol over the Department which includes the Office ofthe Secretary of Defense, the Chairman ofthe Joint Chiets of
‘Stuff andthe Joint Staff, three Miltary Departments, nine Unified Combatant Commands, the DoD Inspector General, fifteen
Defense Agencies, and nine DoD Field Activites

‘The Secretary of Defense is the principal defense policy advisor tothe President and is responsible or the formulation of
faenerl defense policy and policy related to all matters of éieet and primary concer to the DoD, and fo the execution of
approved policy. Under the direction ofthe President, the Secretary exercises authority, direction, and control over the
Department of Defense.

‘The Deputy Secretary of Defense x delegated full power and authority to act forthe Secretary of Defense and to exercise
the powers ofthe Secretary on any and all matters for which the Secretary is authonzed to act pursuant to law.

‘The Office ofthe Secretary of Defense (OSD) isthe principal staff element
‘development, planning, resource management, fiscal, and program evaluation responsibilities, OSD includes the immediate
‘offices of the Secretary and Deputy Secretary of Defense, Under Secretary of Defense for Acquistion and Technology, Under
Secretary of Defense for Policy, Under Secretary of Defense for Personnel and Readiness, Under Secretary of Defense
(Comptroller), Director of Defense Research and Engineering, Assistant Secretaries of Defense, General Counsel, Director of|
Operational Test and Evaluation, Assistants tothe Secretary of Defense, Director of Administration and Management, and
sch other staf offices asthe Secretary establishes to assis in carrying out assigned responsibiines.

f the Secretary in the exercise of policy

‘The Military Departments (DoD Directive $100.1) are the Departments ofthe Army. Navy, and Air Force the Marine
‘Corps is apart ofthe Department of the Navy). Each Miliary Department is separately organized under iis own Secretary and
fanetions under the authority, direction, and control ofthe Secretary of Defense. The Military Departmen ae responsible for
‘organizing. taining, supplying. and equipping forces fo assignment to Unified Combatant Commands. (See Char.)

‘The Unified Combatant Commands (DoD Ditective 5100.1) are responsible tothe President andthe Secretary of Defense
for accomplishing the military missions assigned to them. Commanders ofthe Untied Combatant Commands exercise
‘command authority over forces assigned 1 them as directed by the Secretary of Defense. The operational chain of command
‘runs fom the President to the Secretary of Defense to the Commanders of the Unified Combatant Commands. The Chai

‘of the Joint Chiefs of Staff functions within the chain of command by transmaiting tothe Commanders ofthe Unified Combatant
‘Commands the orders ofthe President or the Secretary of Defense. Unified Combatant Commands include the European
‘Command, Pacific Command, Atlantic Command, Southern Command, Special Operations Command, iraegie Command,
Central Command, Transporation Command, and Space Corsmand. See Char.)

‘The Joint Chiefs of Sta JCS) and Joint Staff (DoD Directive $100.1) The Joint Chiefs of Staff, headed by the

(Charman of the Joint Chiefs of Sta, consists of the Chairman, the Vice Chairman, JCS, the Chief of Sta. US. Army, the
(Chief of Naval Operations, the Chief of Sta, US. Air Fore; andthe Commandant of the Marne Corps, and supported,
subject to the authonty,ditection, and contro ofthe Chairman, by the Joint Saf, constitute the immediate mutary staf of the
‘Secretary of Defense. The Chairman of the JCS isthe principal rultary advisor tothe Presiden, the Nationat Security Counc
land the Secretary of Defense. The Chiefs of Service ae the Senior miliary officers of ther respective Services and are
responsible for Keeping the Secretaries ofthe Miltary Departments fully informed on matters considered or acted upon by the
ACS, and are military advisers othe President, the National Security Council, and the Secretary of Defense. The Vice
‘Chairman ofthe JCS performs such duties as may be prescribed by the Chairman with the approval of the Secretary of
Defense. When there isa vacaney in the Office of the Chairman or in the absence or disability ofthe Chairman, the Vice
‘Charman acts as Chairman and performs the duties ofthe Chairman until a successor 1s appointed or the absence or disability
ceases (See Chart)



113

Mr. SNOWBARGER. Let me ask the more disturbing question. It
is not whether or not you are studying dogs or not whether or not
the tests are ongoing, but the hypothesis in general.

Are we studying military dogs to prove that Gulf war veterans
are not sick?

That seems to be the hypothesis of this particular study and,
again, it says to me that we are not giving much credence to those
men and women who came back and are sick; and they are telling
us that the illness began to manifest itself after their service in the

Ms. WINEGaR. I believe that the work to be done under this
project is but one small piece of an overall program, and I think
that to say that we are studying dogs to prove that veterans aren’t
sick is a real extrapolation of one piece of information.

I think it is incumbent upon us to look into a number of different
possibilities, and clearly in a controlled study such as this where
we have, you know, good access to the information about the mili-
tary dogs should provide one more piece of information to us as we
try to unravel what I believe we all understand to be a very com-
plex problem.

Mr. SNOWBARGER. Dr. Feussner, let me ask you to followup on
that, if you would. I mean, it is the Working Group that approved
that study and approved that hypothesis for a study.

Dr. FEUSSNER. Yes. I think that one of the persistent confusing
features about science is that hypotheses are posed as the null;
that is to say, that there is no association. The research is then
carried out to reject the null hypothesis, such that it can accept the
alternative hypothesis.

That is quite confusing and gives the impression that when you
state the hypothesis as the null that is what you believe. It some-
times leads to the misgiving that, how do you ever prove a nega-
tive? It is impossible to prove a negative. That is a convention of
science that is confusing. The goal of the research is to state the
null and then reject it.

It would be simpler if the hypothesis were simply stated as a
positive statement and then the research would either prove that
the association is correct or not.

I have had a chance to explain many research projects. It is not
something that I think we will ever get around, but I think it does
mislead and give the impression that the scientist believes the null
hypothesis, as stated. That’s usually not the issue. That’s the best
I can tell you.

Mr. SNOWBARGER. Well, I guess I can’t argue with convention in
the scientific community other than to tell you it is pretty stupid.
And when Federal dollars are involved on a general basis and
when the health of servicemen is involved in this particular ques-
tion, we would like to think that—this gives the impression that
we don’t believe our servicemen coming back and saying that there
is a problem that was related to their service. And it sets up the—
it sets up the wrong impression about how we feel about our veter-
ans and their service and puts us, obviously, in a very awkward po-
sition, when it seems to me it is just as easy to set out the—not
the null hypothesis, but I guess the positive hypothesis and prove
or disprove that.


122

came to Washington, I was the Chief of the Clinical Research
branch where we investigated the health effects of ambient air pol-
lutants on the lungs and on the nervous system.

Mr. SHays. Were you concerned about low-level exposure when
you worked there?

Mr. GERRITY. Absolutely. You know, the ambient levels ——

Mr. SHAYS. Why was there concern about low-level exposure in
the private sector?

Mr. GeErRITY. I was in the public sector, sir.

Mr. Suays. I am sorry. What were xen in the public sector?

Mr. GerriTy. U.S. Environmental Protection Agency.

Mr. Suays. Working with the private sector, not—getting the pri-
vate sector to abide by sensible rules and regulations about expo-
sure to chemicals, correct?

Mr. GErRITY. Correct.

Mr. SHays. OK. Why were you concerned that in the private sec-
tor we don’t want people exposed to chemicals?

Mr. Gerrity. I am sorry, sir, would you clarify that question for
me?

Mr. SHays. It is a simple question. Why, when you worked for
EPA, were you concerned about people in the private sector being
exposed to low-level chemicals?

ir. GERRITY. The charge of the EPA was broader than protection
of the private sector. It actually went to protection of the entire
population of the United States.

ir. SHAYS. I just want to ask about the private sector. Why were
you concerned about the private sector?

Mr. GERRITY. Because I think that the Government has an obli-
gation to protect the health of the citizens of the United States.

Mr. SHays. OK. What would you have to protect them from?
Chemicals aren’t a harm. Spell it out to me. You have the exper-
tise. Say what is the obvious.

What is the obvious? The obvious is that you wanted to make
sure that people weren’t exposed to chemicals.

Mr. GERRITY. What we wanted to make sure of was that the lev-
els to which people would be exposed, because I think it has to be
recognized that——

Mr. SHays. You didn’t mind if they were exposed to low-level
chemicals?

Mr. GERRITY. Well, our job was to determine what level would be
considered safe.

Mr. Suays. OK. And low-level was safe?

Mr. Grrrity. It depends upon how you define low-level.

Mr. Suays. OK.

Mr. GerriTy. But what I wanted to say was that, as you pointed
out yourself, for different chemicals, tl 's—

Mr. Suays. I am ing about Dr. Newton. You didn’t point that
out to me and you have expertise. The honest answer and the
more precise answer would have been, there are some low-level
chemicals that can lead to chronic illness and death. That’s the
honest answer. And it doesn’t take a rocket scientist to know that.
We already know it.

And instead, you——

Mr. SANDERS. Dr. Gerrity, do you know that?


127

Mr. KucINICcH. You know, is there monitoring going on right now
with the new troop deployment? Is that happening? How?

Ms. WINEGAR. We have not yet fully implemented all the plans.

Mr. KucINIcH. I am sorry. Wait a minute. Mr. Shays, you know
I have always been very patient at these meetings, but you just
gave me—the doctor gave me a very short answer to that long

juestion, which was yes. Now I am getting an elaboration of it that
loesn’t seem to be quite yes.

Dr. FEUSSNER. My fault. I was saying yes to the question about
us communicating and discussing these issues.

Mr. KucINICH. What is being done right now to make sure that
this doesn’t keep happening, that we don’t create thousands of
more victims?

Ms. WINEGAR. Well, we in the Defense Department are currently
in the process of developing and executing detailed plans, and as
was indicated in a hearing a couple of weeks ago by Mr.
Christopherson, who is the principal deputy in Health Affairs,
when questioned about the specific issue of widespread use of the
anthrax vaccine, he indicated that the Defense Department has not
undertaken that initiative yet simply because we do not have all
the detailed plans in place.

I think that we have made a full and honest commitment to the
members of the military to have all of those plans in place for their
individual medical records, for the records of their deployment posi-
tions, for all the types of information that we can gather. We cer-
tainly will try to do whatever we can for those things that are
under our control.

Many of the things, I think, are beyond our control, and I think
that we have admitted that and need to do as best we can to iden-
tify the things that we know about. That’s our commitment at the
moment. To make a guarantee that there won't

Mr. KUCINICH. Who is in touch with whom? Who from the health
part of this is in touch with the people who are doing the deploy-
ment? What is the communication that is going on?

Dr. FEUSSNER. Well, the clinical arm in VA is headed up by Dr.
Murphy, and she is in contact with her DOD counterparts on the
predeployment planning issues.

Mr. KucINnicH. And are we going to—and are we—so who is in
contact on the predeployment planning? Who did you say it was?

Dr. FEUSSNER. The person who represents VA is Dr. Murphy.

Mr. KucINICH. And they are now working with whom?

Ms. WInEGAR. I am sorry. Would you repeat that?

Mr. Kucinicu. Who is Dr. Murphy working with?

Dr. FEUSSNER. Health Affairs?

Ms. WINEGAR. Well, there are, within the Department of Defense,
the Assistant Secretary for Health Affairs working with the Joint
Staff; and a number of other offices are making the plans and look-
ing at how we are going to keep the detailed records.

‘he VA is used as a consultant and a wealth of knowledge on
that, but it is not their direct responsibility for the deployment
issues.

Mr. KucInicu. I understand that.

Mr. Chairman, I think, with the Chair’s permission, it would be
very helpful for this committee to receive a report on a chain of


151

ammunition and in residues from the use of this ammunition);
pesticides and insect repellents, chemical and biological warfare
agents; and compounds and particulate matter contained in the
extensive smoke from the oil-well fires at the end of the war.
Over 100,000 of the approximately 700,000 Gulf War veterans have
participated in health examination programs that the Department of
Defense (DOD) and the Department of Veterans Affairs (VA)
established between 1992 and 1994. Of those veterans examined by
DOD and VA, nearly 90 percent have reported a wide array of health
complaints and disabling conditions, including fatigue, muscle and
joint pain, gastrointestinal complaints, headaches, depression,
neurologic and neurocognitive impairments, memory loss, shortness
of breath, and sleep disturbances. Some of the veterans fear that
they are suffering from chronic disabling conditions because of
exposure during the war to substances with known or suspected

health effects.

The federal government, primarily through DOD and VA, has sponsored
a variety of research on Gulf War veterans’ illnesses. DOD's
research is one component of a broader agenda coordinated under the
aegis of the Persian Gulf Veterans' Coordinating Board (PGVCB),
which comprises the Secretaries of the Department of Health and
Human Services, VA, and DOD. The details of this agenda are

described in the PGVCB publication entitled A Working Plan for


155

at the time of our review. The results of some studies will not be

available until after 2000.

By the time research was accelerated and broadened, opportunities
had been missed to collect critical data that researchers cannot
accurately reconstruct. Even efforts to measure the chemical
content of the oil-fire smoke, begun only 2 months after the fires
began burning, were initiated after most troops had left the
affected areas and the climatological dynamics were different.
Consequently, researchers had to use statistical models of the
behavior of smoke plumes in order to infer the ground-level
exposures experienced by the large numbers of troops who had
departed by the time they began collecting data. Even if such
models could accurately explain the behavior of the smoke plumes,
they had not been validated as measures of individual exposure, and
their accuracy for this purpose could not be presumed. Similar and
even more serious problems were caused in the measurement of other
exposures by the failure to collect data promptly and maintain

adequate records.*

The delay in starting research has also hindered accurate reporting

of exposures by Gulf War veterans. At the time of our review, 6

(GAO/NSIAD-97-136,

*See i

and Institute of Medicine

5 (Washington, D National Academy

Press), 1996.


CONTENTS

Hearing held on February 24, 1998 ... fesse
Statement of:

Feussner, John, M.D., Chief Research and Development Officer, Depart-
ment of Veterans Affairs, accompanied by Timothy Gerrity, Special
Assistant to the Chief Research and Development Officer; Anna John-
son-Winegar, Director, Environmental and Life Sciences, Department
of Defense; Drue H. Barrett, Ph.D., Division of Environmental Hazards
and Health Effects, National Center for Environmental Health, Centers
for Disease Control and Prevention, U.S. Public Health Service; and
Sheila Newton, National Institute of Environmental Health Sciences,
Department of Health and Human Services .. 4

Hei , Donna, Ph.D., Director, Planning ant
counting Office, accompanied by Kwai-C) "Cheung Che Chan, BE Director Sp ny Special
Studies and Evaluation, General Accounting Office,

Sharma, Ph.D., Assistant Director, Special Studies and FRalugtien
General’ Accounting Office; Robert Haley, M.D., director, Epidemiology

and Scientific rap thics Laboratory, University of Texas Southwestern
Medical Center; Danie Clauw, chief of rheumatolo;

town University 1001 of Medicine; and William Reeves, ‘Srench
Chief, Viral Bednthons, Center for Disease Control and sp MD. Brane 146

Letters, statements, etc., submitted for the record by:

Barrett, Drue H., PhD. Division of Environmental Hazards and Health
Effects, National Center for Environmental Health, Centers for Disease

Control. and Prevention, U.S. Public Health Service, prepared state-

ment of .. 52
Clauw, Dai logy.
School of M statement of... 183
Feussner, John, MD D., Pot ief Research and De
ment of Veterans Affairs: 67
7
175
Hetvilin, Donne, pared mn ug
qunting | ice, prepa statement of
Johnson: ar enne Anna, Director, Enviror
partment of
DOD Miltary ‘working dog evaluation fact sheet 106
DOD organizational structure 129
Persian Gulf veterans health research project update sheet 109
Prepared statement of ... 24

dip


145

Mr. SANDERS. OK. So you are pretty definitive on that. At this
point there are no plans?

Ms. WINEGAR. That is correct.

Mr. SANDERS. What about your response to the FDA filing in
September? Does that mean anything to you?

Ms. WINEGAR. Our response to the interim rule, or our re-
sponse——

Mr. SANDERS. Yes.

Ms. WINEGaR. Yes. I indicated that we would make that avail-
able to you.

Mr. SANDERS. You would make that available to us?

Ms. WINEGAR. Yes.

Mr. SANDERS. But what I am hearing you saying is that in terms
of the present military situation, you have no—you are not intend-
ing to go to the FDA for the waiver of the use of pyridostigmine
bromide?

Ms. WINEGAR. That is correct.

Mr. SANDERS. Thank you. That’s all I have,

Mr. Chairman.

Mr. SHays. I do want to say to you that I know that there is
enough blame to go around on this issue. Congress was asleep, I
was asleep, we all were asleep on this issue. My big concern is the
eagerness in which we try to undo the past and move forward.
With that, I thank all of you for your participation.

We will now call on our second panel. We appreciate the patience
of our second panel, as well as the patience of our first panel.

Dr. FeuSSNER. Thank you, sir.

Mr. Suays. Our panel consists of testimony from five people and
six will sit on the panel. Excuse me, four testimonies: Dr. Heivilin,
Director of Planning and Reporting, General Accounting Office, ac-
companied by Kwai Chan, Director of Special Studies Evaluation,
General Accounting Office, and Sushil Sharma, Assistant Director
of Special Studies and Evaluation, General Accounting Office; Dr.
Robert Haley, director, Epidemiology and Scientific Graphics Lab-
oratory, University of Texas Southwestern Medical Center; Dr.
Daniel Clauw, chief of rheumatology, Georgetown University
School of Medicine; and Dr. William Reeves, Branch Chief, Viral
Exanthems, Center for Disease Control and Prevention.

[Witnesses sworn.]

Mr. Suays. For the record, all witnesses have responded in the
affirmative.

We will start, I think, by the way I called you. Do you remember
how we started? We will start with Dr. Heivilin.


106

FACT SHEET
DOD Military Working Dog Evaluation

Indicators of Human Disease from Persian Gulf War Service:
A Study of Military Working Dogs Deployed in Operations
Desert Shield/Storm

The Department of Defense (DOD) is conducting a
comprehensive evaluation to determine if any diseases exist
in Military Working Dogs (MWDs) deployed during the 1990-91
Persian Gulf War that do not exist in non-deployed dogs.
Both populations of animals will be evaluated following
completion of a working career. No dogs have been or will
be euthanized because of this evaluation. MWDs die of
natural medical causes following a working service that
usually lasts 10-12 years or are euthanized, based on the
clinical judgement of a veterinarian, due to debilitating
and incurable diseases that occur in all aged dogs.

MWDs with Persian Gulf War service inhabited similar
environments as U.S. Armed Forces service members. At the
Armed Forces Institute of Pathology, the American Registry
of Pathology funded a pilot protocol in 1994 enabling the
early implementation of a data collection system that will
include pathologic, demographic, temporal and clinical
findings from initially identified PG MWD cohort and
matched comparison MWDs. This pilot protocol expired in
1995, The current protocol title is: Indicators of Human
Disease from Persian Gulf War Service: A Study of Military
Working Dogs Deployed in Operations Desert Shield/Storm.
The hypothesis (null) to be tested is that in final
analysis, there will be no significant differences in
clinical or pathologic diagnoses between the Persian Gulf
War cohort and the comparison group.

Methodology: This evaluation includes retrospective
and prospective components. Retrospectively, the medical
and training records of the 118 MWDs that deployed to the
Persian Gulf, and 472 non-deployed MWDs matched four to one
based on age, gender and breed, will be abstracted for the
following variables: animal identification; age at death;
date of death; breed; gender; location during the time
frame 1 August 1990 to 31 December 1991; and duration of
deployment. Parameters being assessed include: clinical,
clinicopathological, autopsy findings, histopathological,
toxicological (if indicated) and epidemiological.


66

in light of the threat that has been described to us.
Mr. Towns. And you will submit a copy of that for the record?
Ms. WINEGAR. Yes, we will.
Dr. FEUSSNER. Yes, we will, sir.
(The information referred to follows:]


52

Mr. Chairman, thank you for the opportunity to review with the Committee the
Department of Health and Human Services’ (HHS) involvement in the coordinated Federal effort
to address the health concems of Gulf War veterans and our corresponding research activities in
this area. Iam Dr. Drue Barrett, Chief of the Veterans’ Health Activity Working Group in the
Division of Environmental Hazards and Health Effects, National Center for Environmental
Health (NCEH), Centers for Disease Control and Prevention (CDC). I serve as CDC’s liaison to
HHS on Gulf War issues and I am a member of the Research Working Group of the Persian Gulf
Veterans Coordinating Board.

NCEH has been designated as the lead Center at CDC for addressing Gulf War veterans’
health concems, however other Centers within CDC have also been involved in this effort,
including the National Center for Infectious Diseases, and the National Institute of Occupational
Safety and Health (NIOSH). Besides CDC, other agencies within HHS have also contributed to
addressing the health concerns of Gulf War veterans, including the National Institutes of Health
(NIH) and the Agency for Toxic Substances and Disease Registry (ATSDR).

Coordination of Federal Research Efforts:

There has been HHS representation on the Research Working Group since its inception.
In addition to CDC, the Office of the Secretary and NIH are represented. Through its
membership, HHS has been involved in providing guidance and coordination for the Department
of Defense (DoD) , the Department of Veterans Affairs (VA), and HHS research activities
relating to Gulf War veterans. Specifically, this has included assessing the state and direction of
research, review of government research concepts as they are developed, identification of gaps in

factual knowledge and conceptual understanding, and providing recommendations regarding


173

that these three studies in the New England Journal of Medicine
are seriously affected by three biases which, in effect, based on
data that is actually in those studies, turned evidence, the real ef-
fects, real differences between the two populations into conclusions
that there were no differences.

There are the three biases. First, the researchers calculated sta-
tistical significance levels incorrectly so as to make it harder to find
significant differences between the two Sroups. They handicapped
it by using the wrong statistical significance formula. I am not say-
ing they did this on Purpose. I think it was totally unconscious.

econd, they failed to correct for the fact that the deployed troops
are all well. They had to be well to go to the war. So therefore, all
the people who were sick before the war, who have been going to
the hospital and maybe the possibility of dying, they had to stay
home because you can’t go to the war if you are about to die or if
you are going to the hospital. This we call the “healthy warrior ef-
fect,” because you have to be healthy to be a warrior. Well, by com-
paring just the deployed and all the nondeployed, you see you have
stacked it against finding a difference related to illness from the
deployed. So the two groups come out equal after the war. Well,
that doesn’t mean that there is not an illness in the deployed.

Third, they failed to measure hospitalization and birth defects in
the sickest Gulf war veterans who were discharged soon after they
got home from the war because they were too sick to be a soldier
and they didn’t follow those up, so all that was lost.

Now, these biases are still present in studies that are comparing
deployed and nondeployed, such as the big VA followup study. That
is influenced by these three kinds of biases and is very likely to
show nothing. Also, without a case definition, treatment studies are
not going to show anything, because you are lumping together
large numbers of people. Some of them have the illness and many
others don’t.

Two other points.

Mr. SHays. Just to be clear, on those two points we will conclude,
because have you gone 10 minutes now so you need to conclude.

Dr. HaLey. Two other points. Isn’t it interesting that all of this
time we have been debating that maybe low-level chemicals may
have caused brain damage and yet the CCEP and the VA’s Gulf
war diagnostic protocol exam do not include tests that could show
the type of brain damage that would result from neurotoxic expo-
sure? Also, the peer review groups; this is not only related to mili-
tary and VA people.

Scientists out there in the world also do not believe this is a real
disease. They believe that it is stress, that it is complaining veter-
ans who are trying to get benefits. That is the strong, ingrained be-
lief that has been embedded by a big PR campaign from the gov-
ernment.

In that circumstance, I have sat in a peer review panel that was
looking and evaluating Gulf war research studies. In that panel,
the other side is sitting around and saying well, of course, this is
due to stress; and I brought up, well, maybe could it be due to
chemical exposures? Oh, are you kidding? That’s just crazy. And
then the decisions they made about peer review I felt were highly
biased by that view that they brought in. So I am not sure we are


101

Ethically, there are basically four arguments that
servicepersons should take protective agents without being given
the opportunity to refuse to consent: First, this is necessary to
maximize the likelihood that the US military effort will succeed.
As stated, if US troops were decimated after Iraq used chemical or
biological weapons, hardly imaginable harms to persons in other
countries and this one could occur. Second, this is necessary to
protect inordinate numbers of servicepersons' lives which would be
lost if Traq used these weapons. Third, this is necessary for all
servicepersons to fulfill the implicit promise they have made to
other servicepersons that they will sacrifice their lives if
necessary for the mission or their benefit. In this case, of
course, the sacrifice required to save the mission or other
servicepersons is not their lives but their autonomy to refuse to
consent to taking these protective agents. Fourth, this is
necessary for the military to fulfill its promise to all
servicepersons to do everything possible to protect their lives.

What are the opposing arguments? First, it can be argued that
protective agents which have not been fully tested should not be
given at all. Whether these agents should be given should depend
primarily on whether these agents most likely would save large
numbers of servicepersons' lives if Iraq used chemical or
biological weapons, but do little harm if Iraq did not. As stated,
when the possible need for protective agents initially became
apparent, medical experts in the DOD and FDA reviewed the available
data on the effects of these agents on humans in other contexts and

on animals. On the basis of this review, the DOD determined that


26

Coordinating Board (PGVCB). Because of possible links among environmental factors and
GWV1, the Environmental Protection Agency provides a member on the RWG.

The Department of Veterans Affairs, the responsible agency for coordination of GWVI.
research for the Federal Government, submits an Annual Report to Congress on the results and
progress of research activities undertaken or funded by the Executive Branch of the Federal
Government on Persian Gulf veterans illnesses. The PGVCB-RWG has published two editions of
“A Working Plan for Research on Persian Gulf Veterans’ Illnesses” (1995, 1996), and a third
addition (1997) is in press. In accordance with section 769 of the National Defense Authorization
Act for Fiscal Year 1998, the Secretary of Defense will also submit a report on “Effectiveness of
Medical Research Initiatives Regarding Gulf War Illnesses” to the Committee on National
Security, House of Representatives, and the Armed Services Committee, U.S. Senate. These
reports, collectively, represent the definitive sources of information on GWVI research, significant
research findings, and recommendations for additional research.

T now wish to provide you with the Department's view of the operations strategy, objectives,
and agenda of the PGVCB-RWG, as well as the status of current and projected Defense GWVI
research program.

The PGVCB-RWG provides the overarching policy and guidance linking the overall research
and management efforts by DoD, VA, and DHHS into a comprehensive and integrated national
research program. The DoD supports the guidance, oversight, and assistance of the RWG, The
research on GWVI is a complex and difficult undertaking that does not lend itself to simple or
single-agency approaches. The lack of a yet defined causal relationship to the illnesses cannot be
allowed to deter our national research effort to find solutions that will benefit afflicted veterans
now, and minimize related illnesses during future military operations. The PGVCB -RWG
strategy involves a multidisciplinary approach along many different and novel scientific lines by
‘scientists and clinicians in Federal, academic, and private institutions.

The RWG is charged with:

‘© assessing the status and direction of research;

© identifying deficiencies in knowledge and concepts, testable hypotheses, and potential
research approaches;

© reviewing research concepts and disseminating scientifically peer-reviewed research
information; and

© ensuring that appropriate peer review and oversight are applied to GWVI research

The RWG’s operational approach has been to work collectively with the DoD, VA, and
DHHS in assessing research priorities, The Federal investment in GWVI has been guided
primarily through the coordinating efforts of the RWG as expressed in the “Working Plan.” The
major influences on this Plan and the reason for frequent updates are new research findings,
emergent risk factors, recommendations of expert oversight groups, Public Law, and
Congressional reports. These factors and the disciplined approach being followed have enabled
the RWG to effectively assess and make sound recommendations to DoD, VA, and DHHS on the


22

a brief curriculum vitae for the principal investigator and any key
personnel.

Research program directors oversee the review of these proposals
and look at several factors, including the following: No. 1, military
and program relevance; No. 2, research objective; No. 3, scientific
excellence; No. 4, qualifications; No. 5, facilities; and No. 6, budget.
The final stage of the evaluation is the establishment of a relative
order-of-merit list which is based both on military relevance and
scientific merit evaluations.

The project officer and the contracting staff review the comments
from the Research Working Group before they begin any negotia-
tions with potential contractors.

In addition to full and open competition, as I have mentioned,
there are occasions when noncompetitive awards may be made to
support program administration and management, to fulfill sole-
source requirements for unique capabilities, including those di-
rected by the Congress, and to conduct intramural Federal labora-
tery. research. Examples of such awards include using contract ve-
hicles for study and management assistance, contracting with the
National Academy of Sciences for assistance to the DOD, and the
conduct of epidemiological studies of veterans who were in the vi-
cinity of the Khamisiyah demolition, as well as studies in DOD fa-
cilities that have specialized containment facilities, equipment and
standard operating procedures for work with chemical or biological
warfare agents.

During this last year, the Director of Defense Research and Engi-
neering took several actions to increase the visibility and oversight
of all Department of Defense research efforts on Gulf war veterans’
illnesses, as well as to facilitate program management and integra-
tion with the Research Working Group. These actions include, first,
taking steps to establish a single Defense program element and
project in fiscal year 1999 with 1998 being a transition year. Cur-
rently, defense research on Gulf war veterans’ illnesses is sup-
ported under multiple Defense-wide and Army research develop-
ment test and evaluation program elements. We feel that the es-
tablishment of a single Defense line for Gulf war veterans doing
the specific research should improve DOD oversight and expedite
congressional review, since all program accomplishments, plans
and resource information will appear now as a single program on
the RDT&E budget justification Sheets.

Second, we chartered a Working Integrated Process Team on De-
ployment Toxicology in November 1997. The purpose of this team
is to review current deployment toxicology initiatives and to de-
velop a recommendation regarding. appropriate DOD-level sponsor-
ship and oversight of related policy issues, doctrinal matters and
requirements generation.

Finally, we have incorporated a DOD-wide review of Gulf war
Veterans’ Illnesses research in our annual technology area research
and assessment process. This review process is utilized by the Di-
rector of Defense Research and Engineering to obtain advice and
recommendations from »utside experts to help us guide our pro-

‘am.
Let me conclude my statement by noting that it has not yet been
5 years since the formation of the Research Working Group to co-


105

Let me followup with a question on animal studies. I found this
one rather fascinating.

Dr. Winegar, if you could help me with this one, there is a De-
fense Department study that was approved by the Working Group,
and it has spent about $262,000 to date. It doesn’t look like it is
using money in fiscal year 1998, so perhaps this study is done at
this point. But the hypothesis that it was testing was that, “In the
final analysis, there would be no differences in the diagnosis be-
tween the Gulf military working dogs cohort and the comparison
group of dogs which never deployed to the Gulf War.”

According to public reports, the dogs no longer in active service
are being observed and posthumously examined. First of all, what
is the status of that study?

Ms. WINEGAR. I don’t have the details as to whether that study
has been completed or not, or whether we have received a final re-
port, but I will be happy to provide that information to you.

Mr. SNowBaRGER. OK. The report that we have indicates that it
is ongoing, but again, without any expenditures expected in fiscal

ear 1998, so I am presuming the research has been done; it
is a matter of analysis at this point, I would presume.

Ms. WINEGAR. it could be, but I will have to verify that.

Mr. SNOWBARGER. Well, OK.

[The information referred to follows:]


162

Despite the fact that in 1994, Congress directed DOD and VA to
research treatments for ailing Gulf War veterans, such research has
largely not taken place. While 61 of the 91 federally sponsored
studies (67 percent) were classified as epidemiological by the
Persian Gulf Veterans Coordinating Board, only three of the studies

had focused primarily on identification and improvement of

treatments for these illnesses.

Our review indicated that most of the epidemiological studies have
been hampered by data problems and methodological limitations and
consequently may not provide conclusive answers in response to

their stated objectives, particularly in identifying risk factors

or potential causes.

Measurement of Exposures Is Problematic

The research program to answer basic questions about the illnesses
that afflict Gulf War veterans has at least three major problems in
linking exposures to observed illness or symptoms. First, it is
extremely difficult to gather information about unplanned exposures
(for example, oil-fire smoke and insects) that may have occurred in
the Gulf. And DOD has acknowledged that records of planned or
intentional exposures (for example, the use of vaccines and

pyridostigmine bromide to protect against chemical/biological

14a


165

Several investigators were also relying on a model developed by the
U.S. Army Environmental Hygiene Agency for assessing exposures to
components of oil-fire smoke through the combination of unit
location data with information from models of the distribution of
oil-fire smoke. However, this model requires the use of unit
location as a proxy for exposure, and the validity of this approach
is unknown. The Presidential Advisory Committee has noted, "DOD's
Persian Gulf Registry of Unit Locations lacks the precision and

de}

1 necessary to be an effective tool for the investigation of

exposure incidents."

Case Definition Is Complicated by Presence of Nonspecific Symptoms

Another major hurdle to the development of a successful research
agenda has been the difficulty in classifying symptoms into one or
more distinct illnesses. Some veterans complain of
gastrointestinal pain, others report musculoskeletal pain or
weakness, and still others report emotional or neurological
symptoms. As explained previously, development of one or more
specific case definition is essential to conducting certain types

of epidemiological studies.

The VA collected some data on symptoms beginning in 1992 with the
initiation of its registry. However, these efforts to collect
information about symptoms and exposures from registry participants

were limited and nonspecific. This constrained VA's potential use

17


169

recalled information from actual differences in the frequency
of exposures. As a result, findings from these studies may be

spurious or equivocal.

-- Classifying Gulf War veterans’ symptoms and identifying their
illnesses have been difficult. From the outset, the symptoms
reported have been varied and difficult to classify into one
or more distinct groups. Moreover, several different
diagnoses might provide plausible explanations for some of the
specific health complaints. It has thus been difficult to
develop one or more working case definitions to describe

veterans undiagnosed complaints.

RECOMMENDATIONS

Because of the numbers of veterans who have experienced illnesses
that might be related to their service during the Gulf War, we
recommended in our report that the Secretary of Defense, with the
Secretary of Veterans Affairs, give greater priority to research on
effective treatment for ill veterans and on low-level exposures to
chemicals and other agents as well as their interactive effects and
less priority to further epidemiological studies.

Mr. Chairman, that concludes my prepared remarks. I will be happy
to answer any questions you may have.

(713019)

al


34

decreases the level of permethrin in the central nervous system. The importance of such
interactions led the Department to solicit additional research proposals addressing the
toxic effects of simultaneous exposure to different agents and prophylaxes

Summary of Recent Recommendations for GWVI Research

Thave already mentioned several areas of GWVI-specific research that we are executing. At
this point I want to highlight for you reo recommendations regarding GWVI research that the
Department is or will be pursuing.

GWVL-related research will focls on increasing the understanding of deployment-related
risk factors known to be associated with GWVI. Studies are needed to identify the
confluence of cognitive, emotional and physical factors that produce chronic, nonspecific
symptoms and physiological outcomes typical of the undiagnosed illnesses of some Gulf
War veterans.

Research will continue to investigate persistent uncertainties related to long-term health
consequences associated with exposure to subclinical levels of chemical warfare agents,
and the toxicity and toxic interactions of environmental chemicals, prophylactic drugs,
and military materiel. Clinical trials for assessing the effectiveness of treatments provided
to Gulf War veterans are essential and are currently being planned.

Additional research on appropriate treatments for GWVI will include clinical trials, in
collaboration with VA, for assessing the effectiveness of medical therapies provided to
Gulf War veterans. Such trials can be established for new proposed treatments as clearly
defined, symptom-based medical syndromes are identified.

Many of the health concerns identified after the Gulf War are similar to those associated
with other deployments. Increased knowledge of the potential biological and
toxicological associations between deployment-related exposures and health outcomes,
relative to past, present, and future deployments, would be useful. Such knowledge
could enhance the analysis of potential causes of illnesses; research and development on
effective prevention, intervention, and treatment strategies; and development of an
accurate and effective risk communication plan to inform troops about potential exposure
risks. Comprehensive population-based troop health assessments and exposure
monitoring data and data systems will enable epidemiological researchers to define the
potential associations between exposures and outcomes during future military operations.

Thus, a coordinated capability is needed to apply epidemiological research to determine
whether deployment-related exposures are associated with post-deployment health
outcomes. A balanced research program targeted at improved prevention, intervention,
and treatment strategies for priority health risk factors and exposures and improved
biologically based dose-response models is also needed. A methodology needs to be
developed to systematically collect population-based demographic and health data to
enable evaluation of the health of all Service personnel throughout their military careers


175

Tam speaking today as a physician and epidemiologist who has been investigating the
Gulf War syndrome full time for over four years as an outsider to the government research
process, I will offer my impression of how the government research process is going, from
the viewpoint of an outsider, with the advantage of not having been caught up in the
government thought process but with the disadvantage of not knowing all the reasons why
things have been done,

My overall impiession is that the government's research effort, though well meant and
painstakingly thought out, has misfired entirely and is showing little sign of getting back on
track in the near future. Here is what I think the problem is.

As our troops retumed from the Gulf War, tens of thousands began complaining of
hard-to-express symptoms within a few months of their retum. We now know that it may
have affected 10 to 20 percent. In anybody's book, this was an epidemic and needed to be
approached with the standard method for an epidemic investigation. This investigatory
approach was developed into an standard “fire drill* by CDC over the past 30 years.

Sure enough, in late 1991 and 1992 epidemiologists from the Naval epidemiology unit
in San Diego and others immediately went out to affected units and performed initial
descriptive epidemiology that gave a good picture of the problem. At that point, someone
should have taken "step 1" of the standard epidemic investigation fire drill by writing down a
‘case definition of the Gulf War syndrome and then following through by performing a case-
control study in one of the affected units, identifying risk factors reported by the cases but
not by the controls, performing animal studies to test the biological plausibility of the risk
factors, and so on. In other words, they should have performed a standard epidemic
investigation.

In fact, this almost happened. In late 1993, Dr. Ronald Blanck, who is now Surgeon
General of the Army, commissioned Dr. Jay Sanford, one of the greatest experts of military
medicine of the past half century and a competent epidemiologist, to formulate a case
definition of the Gulf War syndrome. He did it and proposed a case-control study to test it.
However, in early 1994 the process got derailed. The Sanford case definition was shelved,
and no case-control study was done.

Simultaneously, the CCEP was inaugurated, and the decision was made to put tens of
millions of dollars into performing medical examinations on individual active duty soldiers
who were encouraged to step forward. This clinical approach, performed on tens of thousands
of troops, provided no useful insight over and above what was already known, But it also
drained away the energy and resources that might have gone into case-control studies, which
could have discovered the nature of the Gulf War syndrome and the cause of the epidemic.

At the same time, a far reaching policy decision was made to the effect that 1) there is
no single epidemic disease, 2) the soldiers’ symptoms are due to post-traumatic stress disorder
(PTSD), 3) large epidemiologic studies need to be done to prove it, and 4) a public relations
campaign should be waged to convince the American people of this explanation. Accordingly,
orders came down to doctors throughout the military and VA systems that they must not write
down a diagnosis of "Gulf War syndrome,” and new protocols were developed to treat
"stress." It became The Policy.

I believe that what happened after that was a pervasive exercise in, what is called,
“conservation of belief." That is, all incoming information that would challenge the belief was
unconsciously filtered out, all studies were designed to confirm the lack of physical effects,

2


115

A couple of months ago I was at a meeting with veterans in
Springfield, VT, in southern Vermont, and on Saturday, just this
week, I was in a meeting with veterans in Burlington, V[—the
first meeting, about 20 veterans; the second meeting, about 50 vet-
erans. I talked to the veterans and said, How are things going?—
they were all from the Gulf war—and this is what they told me:
In Springfield, sitting around the room with 20 people, I said, Tell
me about memory loss, short-term memory loss. Everybody in the
room started laughing, they started chuckling, because almost
without exception every one of these people who were between 35
and 45, hard-working Vermonters, every one of these people were
suffering from short-term memory loss.

So I want you to tell me whether you think it is a natural thing
for people that age, who are healthy enough to get into the Na-
tional Guard, should be suffering from that?

Then another funny thing happened. We were talking about
other problems that people have, and a lot of guys were saying, you
know, I go into a supermarket and I walk past the detergent sec-
tion—you know how they have that funny smell from detergents—
and they said, When I smell that, I get sick. Then they were talk-
ing about those scented candles, you know about scented candles,
and they were all laughing about that. When they are around
scented candles, they get sick. When their wives wear perfume,
they get sick.

low, let me read you just some testimony from the committee
report, and this comes from Sergeant Martin, who testified before
our committee. He said, “I suffer from excruciatingly painful head-
aches, memory loss and severe diarrhea, mood swings. I violently
vomit if I smell perfumes, vapors or chemicals. I get lost and forget.
where I am sometimes.”

In Burlington, in the meeting 2 days ago, we talked about short-
term memory loss; almost every hand in the room went up. Now,
T have a hard time understanding how healthy people 35 to 40
years old suffer from short-term memory loss.

A guy who is in a car, he says, with his family, they are out on
a vacation having a great time, wife and two kids, suddenly he can-
not remember where he was going. People cannot remember the
simplest things.

Now, I want you to tell me about your views and whether you
have done any work or you believe even in the concept of multiple
chemical sensitivity. Throughout the testimony and in my own ex-
perience with Vermont vets, we hear things like, this is from Mi-
chael Donnelly, a major who is now very, very ill, he says and I
quote, “I was exposed to malathion fogging, an organophosphate

sticide used for mosquito control, while jogging in the evenings.
PStarted to have serious health problems.”

In other words, time after time, we are hearing people—auto-
mobile mechanics no longer can deal with gas fumes, can’t deal
with oil fumes. A guy was telling me the other day in Vermont,
who works in the Brest, he cannot deal with the odor of trees, if
you can believe it.

I want you to tell me what you have learned. Is this true? Is
there any work that you have been doing on this? I would like you
to tell us whether at this point in time you believe in the concept


194

sensitivity, where there is an infectious agent that we have yet to
identify.

Going back to what some of the people on the earlier panel said,
I think the problem with these types of treatment trials are to try
to identify the subset of people who have the infectious illness and
put them in the trial of antibiotics, rather than looking at the en-
tire group of people, because I think you would have a very difficult
time showing efficacy of antibiotics if you just looked at all comers
pith Gulf war illness. I think that would be unlikely to be success-
ful. :

Mr. SANDERS. Last question, and anybody can jump in. Dr. Chan,
did you want to say something?

Mr. Cuan. Yes. I think what I would like to say is that from the
previous panel and even the discussion currently, it is closer to
what Nujaia was thinking about. What the previous panel inter-
preted, when we discuss the issue of treatment, was that they were
really thinking about clinical trials and looking for treatment and
having control groups and so on, which is extraordinarily lengthy
in time and cost, and I wrote down on my paper why this was
being discussed. I said, “haven for researchers for years to come.”

I think the answer that is given here is more to what we were
thinking about. Because you have a consolidation of illnesses and
symptoms, and there are specific symptoms that may be treatable
in the short term, possibly the long term, and some that may not
be, and what we are hoping for is that the physicians and those
researchers who are looking into these patients can come out with
positive treatments with which they can actually show progress
and share them among the other physicians.

Mr. SANDERS. Right.

Mr. CHAN. You can’t just announce and say “let’s have a clinical
trial and treatments” and expect physicians to come through with
a proposal, which is not the work that they are doing. I would like
to clarify that point.

Mr. SANDERS. OK. Let me ask Dr. Chan or anybody else. Isn't
it funny, or isn’t it strange that after 7 years, there are not a dozen
different treatment protocols out there; some may work, some may
not work, but we can learn by failures as well as partial success.
Am I missing something?

Dr. HALEY. We actually have a treatment trial going now, in the
Seabees group. As we bring our cases and controls in, the controls
just go home at the end, but the cases we enroll into a treatment
trial. Our research group, based on the study of the symptoms, we
have enumerated five different medications that we think will at-
tack one of the symptoms, one of these variable symptoms that
they have. So as they go on, we are going to enroll them so that
they take one of these medicines for a month, and then they go off
everything for 2 weeks and then they take the next one for a
month. They are randomized and double blinded, and then at the
end at 6 or 8 months we will then know whether these five drugs
attack these symptoms. Let me just say we proposed this to the
Persian Gulf Veterans Coordinating Board ‘and. it was rejected. We
are doing this on private money.

Mr. SANDERS. I am not a scientist, but Mr. Chairman, what Dr.
Haley is expressing, and it seems to me, please others jump in, to


136

harmful in healthy individuals; two, PB was worthless, even coun-
terproductive as a protectant against chemical warfare; and three,
PB was more toxic than sublethal doses of chemical warfare
agents.”

That was his opinion. I am not saying he is right or wrong. You
tell me. Is he right or wrong? Should we be scared?

Dr. FEUSSNER. I think that decisions that were made regarding
that drug suggested that the risks were worth the benefit.

Mr. SANDERS. You disagree with Dr. Tiedt then?

Dr. FEUSSNER. I can’t agree—I think you said that he said that
this drug was worse than toxic warfare agents, and I don’t believe
Ican e with that.

Mr, SANDERS, He said it was worthless, even counterproductive,
as a protectant against chemical warfare; and three, PB was more
toxic than sublethal doses of chemical warfare agents.

I am not saying whether he is right or wrong.

Dr. FEUSSNER. I can’t agree with that.

Mr. SANDERS. OK. Are you doing—I mean, he makes serious
charges. Are we doing work now to say—so that you can come be-
fore this committee to say, he is dead wrong and we know that he
is dead wrong?

Dr. FEUSSNER. Well—

Mr. SHays. How do define “wrong”?

Mr. SANDERS. Picking up on Mr. Kucinich’s point, if he is right,
or half right, we should be very cautious about what happens in
the future.

Yes, Dr. Newton.

Ms. NEWTON. The National Toxicology Program has conducted
studies on pyridostigmine bromide. I do not have the results, but
I can get them.

ot ‘Suays. I need a translation. You need to speak a little more
slowly.

Mr. SANDERS. They have done research. They can get--———

Ms. NEwTON. The National Toxicology Program, which NIEHS is
the lead agency for, has done toxicity studies of pyridostigmine bro-

mide.

Mr. Suays. Did they do those studies?

Ms. Newron. I don’t know.

Mr. SANDERS. Then how do they respond to those—to Dr. Tiedt’s
charges?

Ms. NEWTON. Like I say, all I know is that the studies were
done. I can get you the results.

Mr. SANDERS. I am not saying that Dr. Tiedt is right. I am not
saying that. But he made extraordinarily—he has experience. He
claims that the DOD itself did research which backs up his asser-
tions.

I can’t say if it is right or wrong, but I would hope that you
would be able to tell the soldiers in the United States today t
he is wrong and very clearly wrong.

Now, the last point that I want to make, Mr. Chairman, gets
back to a point that I made earlier that deals with multiple chemi-
cal sensitivity. The chairman was talking about that when he was
in the Connecticut Legislature he was very concerned about the im-
pact of low-level exposure on human health.


7

In it, I showed three pervading biases that were overlooked and that caused the
Tesults to be 180 degrees wrong. These are: 1) the researchers calculated the
statistical significance levels incorrectly so as to make it harder to find significant
differences between the two groups; 2) they failed to correct for the fact that
deployed troops are all well and the soldiers who are sick with chronic diseases
remain at home with the nondeployed group (the "healthy-warrior effect"); and 3)
they failed to measure hospitalization and birth defects in the sickest Gulf War
veterans who were discharged from the service soon after the war. All of these
biases obscured real increases in mortality, hospitalization and birth defects in the
deployed population. These biases are still present in the newly announced VA
‘studies comparing samples of deployed and nondeployed veterans and are likely to
obscure the illness in the future.

5. The scientific review committees who periodically commented on the government's.
progress and who reviewed the studies for scientific journals, themselves convinced
of the Stress Theory, also overlooked these biases and were satisfied not to go
directly at the problem with an epidemic investigation to test a case definition.

6. Despite the nationwide furor over whether troops sustained neurotoxic injuries from
chemical nerve agents and other organophosphate chemicals, the standard CCEP
examination and the VA Gulf War diagnostic protocol examination did not include
tests that could detect neurotoxic brain damage. These include audiovestibular tests
of brainstem function, brainstem evoked potentials, neuropsychological tests like
the Halstead-Reitan battery but not others commonly used, et cetera. When we
performed these on ill veterans meeting our case definition of Gulf War syndrome
and carefully matched controls, they showed evidence of neurotoxic brain damage.
Our results, however, have been shunned because they run counter to The Policy.

7, Recently, as calls for a case definition and an explanation have continued to
intensify, enterprising researchers are pulling out the case definitions of chronic
fatigue syndrome, fibromyalgia, and multiple chemical sensitivity—-never mind
that these are medical terms for civilian conditions that are not understood.

8. I served on a study section peer reviewing grant proposals for government funding
about a year ago. My fellow peer reviewers were mostly prominent scientists with
the best of intentions, but their reviews and the conversations around the table
throughout the day revealed that most believed the stress theory and felt
uncomfortable discussing the possibility that veterans might have been exposed to
chemical weapons, or that the veterans’ symptoms might have a neurotoxic
etiology. Consequently, the grant decisions came out pretty consistent with The

Policy.
9. Thave spoken to VA researchers who felt that their careers might be jeopardized if
they proposed research projects to study neurotoxic hypotheses rather than stress

and others who say they were let go from the VA system for doing so.

‘What explains all of these puzzling phenomena? First, I don't see a conspiracy to
avoid the costs of caring for injured veterans, or covering up culpability for not protecting our
troops in the war. I think if the medical community were convinced of a treatable etiology for
the Gulf War syndrome, the costs of caring for veterans would be born readily, and from my

4


58

Veterans.” This investigator and his collaborators have been following cohorts of Gulf War
veterans and Gulf War-era veterans for several years and have shown higher prevalences for a
variety of symptoms in veterans who were deployed to the Gulf as opposed to those deployed
only as far as Germany. This has included pilot data showing poorer neuropsychological test
scores in Gulf-deployed versus non-Gulf-deployed veterans.

In this study, functional magnetic resonance imaging (fMRI) will be used with 120
subjects to examine possible differences in brain activation within specific neuroanatomical areas
between Gulf-deployed and non-Gulf-deployed subjects with different levels of symptoms.
Patterns of activation of {MRI in Gulf War veterans challenged with a test of working memory
will be compared to veterans not deployed to the Gulf (n=40); and between high symptom Gulf
deployed veterans (n=40) and low symptom Gulf-deployed veterans (n=40).

In addition, a new data-driven mathematical technique, Logical Analysis of Data, (LAD)
will be used to examine previously collected symptom data (n=300) to see if there is a set of
complaints characteristic of service in the Gulf region useful for determining etiology or for case
definition. This component of the study will be used to identify the most significant items or
patterns of items for discriminating deployed and non-deployed subjeets.

Finally, neuropsychological test results and symptom prevalence measures will be
replicated and verified in a cohort of Danish armed forces. The Danish forces arrived after the
cessation of hostilities. This component of the study will compare neuropsychological function
in Danish troops deployed to the Gulf (n=200) and a comparison sample of non-deployed Danish
troops (n=200); relate neuropsychological test results in the Danish deployed cohort to self
reported exposures while in the Gulf; compare neuropsychological test scores in the Danish and

7


112

PUBLICATION: None
START DATE: Summer 1994 EXPECTED COMPLETION DATE: 12/30/2001

LEVEL OF EFFORT TO DATE:

To Date: Projection to Completion
FTEs 2.5-3.5 95-10
Funding 214,500 165,000 (FY 97)

FUNDING SOURCE: AFIP; USA MEDCOM
FUNDING TYPE: Intermural; P-8
GRANTEE OR CONTRACTOR: NA


16

Not completely. There will always be a requirement for the interim rule. Even
if safety and efficacy benchmarks were identified by the agency for the products under
development today, until these products were actually licensed or approved, they would
still be investigational. ‘The clear threat of new chemical and biological weapons being
developed makes the search for protective agents a continuous process. In the DoD’s
efforts to continually improve medical care and to counter new chemical and biological
threats, there will always be products in development which will not have yet reached
sufficient maturity to be licensed or approved. These products may still require use
while they remain in an IND status, in which case use in connection with military
combat exigencies may raise an issue regarding the feasibility of informed consent.

(3) Civilian populations may require products used in the prevention or
treatment of the serious or life-threatening effects from exposure to toxic chemical or
biological agents, e.g., in the event of exigencies such as the release of toxic chemical
agents in the Tokyo subway system. Thus, should the agency consider identifying the
evidence needed to demonstrate safety and effectiveness for these products which would
apply to both civilian as well as military populations?

The Office of Emergency Preparedness, DoD, and the FDA should work
together to assure that medical personnel can use the best prophylactic and therapeutic
products available against chemical and biological weapons in both the military and
civilian contexts. This should be an urgent priority.


28

Extramural research awards on GWVI may result from an investigator responding to the
USAMRMC open-ended BAA. This open-ended announcement is the USAMRMC BAA 95-1
(http://w ww-usamraa.army.mil/oaa95-1 him). It solicits medical and biomedical research ideas,
with emphasis on those that are most relevant to ongoing Army medical research programs. It
has no specific closing date and investigators are encouraged to submit brief, three to four (3-4)
page preproposals addressing:

the problem to be studied;

significance and/or uniqueness of the proposed effort;

proposed relevance to Defense biomedical and medical research programs;

relative cost information such as project duration, number and type of personnel as
well as estimated levels of effort, and major equipment purchase requirements;

© overview description of any proposed use of animal or human subjects of research; and
© brief curriculum vitae for the principal investigator and any key personnel.

weer

Review Process. Research program directors oversee the review of these preproposals and
cither encourage investigators to submit full proposals or dissuade submission of a full proposal.
If an investigator desires, the preproposal route need not be followed and a full proposal may be
submitted according to proposal preparation instructions provided in the BAA. Proposals
submitted under the open-ended BAA are evaluated by in-house or by in-house and independent
review committees for scientific merit and programmatic relevance against the following factors
(in descending order of importance).

(1) Military and Program Relevance, Does the proposal clearly address a relevant and
significant military related problem that can be solved by research and development
studies? Does the proposed research meet current USAMRMC program needs and goals?

(2) Research Objective, Is the stated objective clear, valid, and logical?

(3) Scientific Excellence. Are the plans, methods, techniques and procedures feasible,
clear, valid, adequately referenced, and state-of-the-art?

(4) Qualifications, Are the qualifications, capabilities, and experience of the proposed
principal investigator and other key personnel sufficient to achieve the proposed
objectives?

(5) Facilities. Are the proposed facilities and equipment, or unique combinations of these,
adequate for the proposed objectives?

(6) Budget, Does the budget reflect the actual needs of the proposed work? Have the
requests for personnel, equipment, supplies and travel been fully justified?

The final stage of the evaluation is the establishment of a relative order of merit list, which is
based on military relevance and scientific merit evaluations. Awards depend upon:


94
16

7. Initiatives since the Gulf War, including current
operations in Bosnia, have improved DoD‘s ability to implement
medical countermeasures under the authority of the current rule,
should that become necessary in the future.

Since the Gulf War, the Department has significantly
improved its capability to monitor the health of military
Personnel deployed by the President to hazardous areas, such as
the current Operation Joint Endeavor in Bosnia. As part of the
“lessons learned” from the Gulf War, DoD has assigned a high
priority to improved documentation of health information,
including administration of medications and vaccines. A number
of initiatives are in progress to enhance capabilities to manage
medical information under field conditions. DoD has established
a task force to address the issue of medical records in a
military theater of operations. Records pertaining to the
results of pre-and post-deployment health screening will be
captured in an automated data base. DoD is expanding the
automated Composite Health Care System (CHCS) medical record
system to include a module for medical records of a deployed
force. Attention is being directed toward developing a mechanism
for computerizing medical data (including classified information,
if and when it is needed) in the field to ensure standardized
record keeping.

In May of 1994, DoD initiated an aggressive, clinical
diagnostic plan, the Comprehensive Clinical Evaluation Program
(CCEP) to offer intensive examinations to Gulf War veterans. The
CCEP has provided an in-depth medical evaluation to eligible
Service members concerned about their health. The CCEP provides
an integrated system to evaluate the health status of service
members who participate in deployments in the future.
Modifications of the program will allow DoD to administer health
questionnaires and conduct medical examinations of groups of
deployed personnel, and collect the information through an
automated process for entry into a centralized data base for
subsequent analysis and interpretation.

Earlier this year, DoD released the Medical Surveillance
Plan for U.S. Ground Forces Deploying to Bosnia, which has
improved significantly the capability to monitor the health of
the deployed force. The plan provided guidance, in conjunction


review programs (e.g., DoD/Department of the Army uses a contract with the American
Institute of Biological Sciences). Abstracts of peer-reviewed proposals, written reviews of
the peer-reviewers, and the scientific merit scores assigned by the peer-reviewers, are
provided to a subcommittee of the RWG charged with providing secondary review of
proposals for relevance. The information provided is redacted for personal and
institutional identifiers so that programmatic review is anonymous. Relevance
determinations are guided by programmatic needs articulated through the RWG process.
In its secondary review the RWG may re-rank proposals based on relevance, but it will not
recommend non-meritorious proposals for funding to any agency.

The RWG continues to work diligently to foster the highest standards of
competition and peer-review for all research on Gulf War veterans’ illnesses.

‘As an operational policy, the Research Working Group works through the line
management authority each department maintains over its intramural scientists, scientific
program managers (responsible for extramural research), and budgets.

By drawing the three departments together, the RWG has been able to jointly
develop a research strategy, jointly serve as a forum for researchers to present ideas and
findings, and jointly respond to emerging research issues and problems. Through the
priority setting processes carried on within the RWG, each department is able to
independently develop approaches to addressing those priorities. These approaches are
then returned to the RWG for joint discussion, resolution, and recommendations. The
RWG has served as an umbrella under which the federal government has been able to
respond to many research issues outside the context of the RWG's regular meetings.

When emerging research issues arise within an individual department, the RWG is


17

THE ASSISTANT SECRETARY OF DEFENSE

MASHINGTON, D.C, 20501-1260

SEP 1 31995

Honorable David Kessler, M.D.
Commissioner of Food and Drugs
Department of Health and Human Services
Rockville, Maryland 20857

Dear Dr. Kessler:

On behalf of the Department of Defense, I submit comments on
the petition filed May 7, 1996, by Public Citizen Litigation
Group requesting that the FDA repeal 21 CFR § 50.23(d), which
allows the Commissioner of Food and Drugs to determine that
obtaining informed consent for the use of an investigational new
drug is not feasible under certain military combat exigencies.

Granting this petition would jeopardize the lives and health
of military personnel and weaken national defense. The
Department of Defense urges that it be denied.

“the DoD comments are set forth in the attachment. To
briefly summarize, when the President orders the deployment of
U.S. military forces, the U.S. Government has a duty to take all
reasonable precautions to bring about a successful completion of
the mission and a safe return of the forces. In today's world,
that duty must include a recognition of the startling
proliferation of chemical and biological weapons among potential
adversaries and terrorist organizations and an obligation to
implement the best possible medical countermeasures.
Implementation of the-best possible medical countermeasures may
require the standardized treatment use of an investigational new
drug or vaccine for all personnel at risk in a military combat
exigency. The current rule's authority to do this is extremely
limited, available only under extraordinary circumstances and
explicitly restricted to advancing the best interests of the
military personnel concerned. The current regulation fully
complies with applicable law and governing ethical standards.

Overall, notwithstanding some difficulties in carrying out
the designed treatment protocols, the uses of the current rule

during the Persian Gulf.War.clearly support the rule's

Encl e2


interest” advocates back home inappropriately accusing the
military of wrongs comparable to Nazi medical experiments. They
might be getting erroneous medical advice from friends or family.
They might be confused by the first-time experience of having a
choice regarding combat medical care. They might put off a
decision until a later possible time or event. Moreover, if the
choice is truly voluntary, they do not need a reason and may not
have one. The fact is that there is no basis to assume that,
among a group of many thousands of people presented with
complicated medical information, most will chose the course all
knowledgeable medical people would consider the only wise one.
And in the middle of large-scale combat operations or
preparations, communication and decision making processes are
anything but ideal.

As an illustration of the problem, assume a deployment for a
major regional conflict, such as the Persian Gulf War, involving
500,000 U.S. troops. Assume further a very good response rate of
80% of these troops providing voluntary informed consent for, to
select an example, botulinum toxoid vaccine. If botulinum toxin
weapons are used in large scale by the enemy, we will have
100,000 troops at considerable risk of fatal injury, with no
alternative treatment available. This far exceeds the total
number of U.S. forces killed in the entire Vietnam War. Failing
to prevent preventable casualties of even a small fraction of
this magnitude would be a human tragedy, a military disaster, and
a national scandal of historic dimensions.

4. The current rule is an extremely limited authority,
requiring case-by-case justification, available only under
extraordinary circumstances, and explicitly restricted to
advancing the best interests of the military personnel concerned.

As the FDA stated in the preamble to the current regulation:

: Because of the paramount importance of informed
consent, only the narrowest exceptions to this requirement
are consistent with FDA's responsibilities and consistent
with the best interests of human subjects. Nevertheless,
FDA has determined that, in the special circumstance that
may be created by the use of troops in combat and consistent
with its obligations under sections 505(i) and 507(d) [of
the Federal Food, Drug and Cosmetic Act], FDA may narrowly


5

cerning sulfur mustard, the nerve agent VX, and the role of the ge-
netic expression of cholinesterases in protecting against
anticholinesterase nerve agents.

Subsequently, DOD published a four-part broad agency an-
nouncement called BAA to amplify research on low-level chemical
warfare nerve agent effects, as well as research on the health ef-
fects of other exposures including insecticides, the nerve agent pro-
phylaxis pyridostigmine bromide, and stress. The BAA resulted in

nding recommendations for 12 new projects valued at approxi-
mately $12 million and covering such exposures as sarin,
pyridostigmine bromide, insecticides, psychological stress and heat
stress, alone and in various combinations.

In March 1997, the VA organized an international symposium in
conjunction with the Society of Toxicology on the health. effects of
low-level exposure to chemical warfare nerve agents. Investigators
from the United States and from Japan to Israel participated in
that conference.

More recently, the sarin terrorist attacks in Japan have provided
an opportunity to study the health consequences of a real-time,
clearly confirmed sarin exposure. A VA investigator has been col-
laborating with Japanese investigators who have conducted follow-
up studies on exposed individuals. These study subjects experi-
enced acute, but mild, symptoms arising from the Tokyo subwa:
sarin attack of 1995. Investigators have studied psychological,
neurobehavioral, and neurophysiological outcomes in these sub-
jects.

Three papers subsequently have resulted from this research and
have been published. These papers provide new insight into the ef-
fects of clinical exposure to sarin 6 to 8 months following an acute
attack. In comparison with matched controls, the exposed subjects
manifest subtle neurophysiological effects that show that sarin may
cause effects on the brain that are sustained for some time follow-
ing clinical recovery from acute effects.

Second, although issues around the potential health impacts on
our troops of potential low-level exposures to nerve agents are im-
portant, there are other health outcomes of concern as well. For ex-
ample, the importance of musculoskeletal conditions among Gulf
war veterans is clearly evident based on the prevalence of these
conditions among veterans reporting to the VA and DOD registries
and on results emerging from a number of research efforts.

Because of the obvious importance of ensuring appropriate and
effective treatment of Gulf war veterans’ illness, the Department of
Veterans Affairs, Office of Research and Development, formed a
planning group charged with developing a program announcement
inviting proposals within the VA system, or in collaboration with
DOD, for multicentered trials for candidate treatments of clear]:
defined medical syndromes or illnesses among subgroups of Gulf
war veterans. The program announcement was issued in January
1998. In addition, VA and DOD are proceeding with the planning
of a joint VA-DOD multicenter treatment trial for chronic fatigue
syndrome and fibromyalgia in Gulf war veterans.

Third, both VA and DOD have undertaken new initiatives that
are focused on neurobiology of stress and stress disorders. These
new efforts include the following: VA and DOD have issued a re-


lll

pathotogic findings and an interpretation of these findings. Remaining wet tissues,
paraffin blocks, microslides and case folder materials will be archived. The pathology
report will be forwarded to the DODMWDVS, Lackland AFB, TX for inclusion in the
MWD's medical record.

All clinical and pathological information collected during the final examination
procedures will be electronically stored in a database for statistical analysis using the
SPSS* statistical program.

Upon completion of initial data and records collection data , a multivariate
analysis of collected variables will be accomplished to determine the effects of age,
gender and breed on those conditions commonly occurring in the entire population of
MWDs. Odds ratios and ninety-five percent confidence intervals will be calculated on all
conditions occurring more frequently in one cohort to determine the effects of the
exposure status on those conditions. Fishers's exact p values will be calculated to
determine statistical significance of any conditions occurring more frequently in one
cohort.

STATUS/ RESULTS TO DATE: Ongoing. We have identified one hundred eighteen
MWDs that deployed to various locations in the PG Theater in support of operations
within the inclusive dates listed above. The AFIP funded a pilot protocol enabling the
early implementation of a data collection system that includes pathologic (including
surgical and post-mortem morphologic changes), demographic, and clinical findings
from initially identified PG MWD cohort and matched comparison MWDs. The pilot
protocol funding expired in 1995,

The collection and analysis of epidemiological data is the primary responsibility of
the US Army Veterinary Corps Officer currently stationed at the DODMWDVS,

Lackland AFB, TX. Records have been collected and reviewed on 78 Persian Gulf
cohort animals and approximately 400 additional dogs that will serve as a comparison
group.

In January 1997, a panel of civilian veterinary medical experts from eight different
academic and industrial institutes met, as an advisory body, with investigators from the
DODMWDVS and AFIP to discuss the project.

‘The Department of Veterinary Pathology, Armed Forces Institute of Pathology,
along with a database management consultant with expertise in SNOWMED
International is near completion of the database system. This database system should
be completed and ready for data entry in February 1998. Computer software and
hardware have been obtained to support this process. The AFIP and the DOD
Veterinary Laboratory at Fort Sam Houston ,TX are storing MWD tissue specimens for
toxicological analysis, if indicated. Electrophysiological myoneural diagnostic
evaluation is ongoing in cohort animals already at DODMWDVS. Muscle biopsies of the
biceps femoris and triceps brachii; and nerve biopsies of the tibial and radial nerves are
currently being collected for electron microscopic analysis at Auburn University.
Approximately 75 % of the PG MWD cohort are deceased; however, information and
records must be collected, collated and abstracted. Clinical and pathological findings
must be entered into the database management system and analyzed in order to draw
conclusions and compare the two cohorts.


81

Report concludes:

The character of warfare has changed. Just as military
planners must assume that antagonists may have armored
forces and combat aircraft, planning for major regional
conflicts must give consideration to the possibility that
adversaries may have NBC [nuclear, biological and chemical}
weapons and the means to deliver them.

When such consideration is given to this possibility,
attention must be focused on identifying the best possible
medical countermeasures to the biological and chemical weapons
threat.

3, Implementation of the best possible medical
countermeasures may require the standardized treatment use of an
investigational new drug or vaccine for all personnel at risk in
a military combat exigency, including those personnel who, for
whatever reason or no reagon at all, would prefer an alternate
treatment or no treatment.

The need to determine the best possible medical
countermeasures may lead in any of a number of directions. Most
likely, the medical community will recommend reliance on well
established preventive or treatment approaches using approved
drugs and licensed vaccines. However, in some cases, there may
be no such option available. In this regard, the development of
prophylactic or therapeutic modalities for chemical and
biological weapons threats is severely hindered by an inability
to carry out human clinical trials of efficacy. Nonetheless,
sufficient evidence of efficacy may be present using a
combination of animal model trials and surrogate endpoint data on
humans. When justified by the safety and efficacy data, DoD
strongly favors approval of a New Drug Application and continues
to believe that the FDA's accelerated approval process, including
the option of marketing limitations, is an appropriate mechanism
for addressing these special military needs.

In still other cases where the best possible medical
approach includes the use of an investigational new drug, it may
not be necessary, depending upon the nature of the risk and other
factors, to use the investigational product on a standardized
basis. For example, in the current Bésnia deployment, military


188

conditions may require a different organizational strategy than those employed to date.
Much of the currently funded research has been of individual projects proposed by
investigators who are pursuing their scientific hypotheses. These investigator-initiated
research projects have the advantage of promoting innovative ideas. But there are
also significant disadvantages to this approach, including the fact that there is
concurrent funding of duplicative efforts, and there is very little coordination between
projects. In most complex medical conditions such as cancer and AIDS we have
realized that there is a need for more integrated approach which can link population-
based epidemiologic studies, physiologic studies, and treatment protocols. | feel that a
similar strategy, modeled after the “institutes” that have been formed to
comprehensively study other complex illnesses, is necessary to study post-deployment
illnesses such as Gulf War illness. These institutes should consist of the best and the
brightest scientists from a number of different disciplines who would work toward a
‘common goal of determining the causes and treatments of these conditions. It would
also seem preferable to have such institutes housed outside of government agencies,
‘or else pressure from patient advocacy groups, competing agencies, or politicians will

hinder the scientific effort which is necessary.


107

Prospectively beginning in 1996, those 39 Persian Gulf
cohort dogs, which remained on active service, and
comparison cohort of 156 non-deployed MWDs will be
relocated to DOD Military Working Dog Veterinary Service
(DODMWDVS), Lackland AFB, TX, when the attending
veterinarian determines these animals are unable to perform
military missions. This process was initiated in order to
conduct comprehensive physical, neurological, behavioral,
radiographic, clinicopathological, electrodiagnostic,
autopsy and histopathological examinations in a
standardized methodology. The above 39 dogs and the matched
comparison group are expected to complete active service
within the next 12-18 months.

This evaluation has not had any impact on the
operational readiness of the DOD working dog program. The
only change has been the administrative procedures to
relocate dogs to Lackland, APB, TX when these animals are
unable to perform military missions.

Generation of data: All MWDs receive semi-annual
physical examinations that include panels of hematologic,
selected serologic, and blood chemical analyses. The
results are posted in the medical record. Complete medical
records from all deceased MWDs in the Department of Defense
are archived at DODMNDVS, Lackland Air Force Base, Texas.
Following the completion of a working career with death
from natural causes or euthanasia for medical reasons,
complete autopsies are performed in accordance with a
standard protocol. Histopathological assessment and
archival of military working dog tissues are completed at
the Armed Forces Institute of Pathology, Washington, DC.

The clinical and pathological information generated
from this effort will be electronically stored in a
database for comparison of these two animal populations and
statistical analysis.


92

14

There were also implementation difficulties in connection
with the uniform provision of information to personnel regarding
pyridostigmine and the preservation of records in connection with
botulinum toxoid vaccines. Efforts to carry out the planned
distribution of revised information packets on pyridostigmine to
the hundreds of thousands of troops deployed throughout the
theater of operations were frustrated by the limited time between
the FDA approval of the protocol January 8, 1991, and the
beginning of Operation Desert Storm a couple of weeks later.

With respect to record keeping and reporting on pyridostigmine,
normal IND record keeping and reporting requirements had been
waived by the FDA in recognition of the logistical realities and
the reliance on self administration of the tablets. After the
cessation of hostilities, several surveys were conducted, with
results reported to the FDA. With regard to botulinum toxoid
vaccine, appropriate record keeping and retention were frustrated
by the Central Command's determination of the need for security
classification regarding biological warfare defense vaccines
(including both the licensed anthrax vaccine and the IND
botulinum toxoid vaccine) .

These several implementation problems establish the need for
improvements, at least some of which have already been made in
the implementation systems and procedures DoD relies upon in
operational deployments. Perhaps most importantly, the treatment
protocol development process needs to include people who are
closer to the reality of the battlefield. However, none of these
implementation difficulties during the Gulf War changes the
fundamental fact that had the enemy used its apparent capability
to deliver chemical or biological weapons, based on the available
evidence of the safety and efficacy of these two IND products and
the lack of an effective alternative treatment, the best medical
countermeasures, as far as the medical establishment of the
Government could determine, clearly included the treatment use of
these products. And, in the context of the pending petition,
nothing that happened during the Gulf War even remotely supports
the argument that military personnel or the Government or the
nation would be better off with the repeal of the current rule.

Some of the other criticisms of DoD and/or FDA actions
during the Gulf War are without foundation. For example,
evidence supporting the safety of pyridostigmine and botulinum
toxoid was and still is quite solid. “Pyridostigmine has been


180

lems with these unexplained symptoms and syndromes, and the in-
appropriate psychiatric attribution of symptoms occurs whether
these individuals are seen in the VA or military facilities or in the
private sector. The important issue in this regard that I think
needs emphasis is that the lack of a single definition for these ill-
nesses or of any laboratory or diagnostic test that can definitively
establish a diagnosis causes considerable problems in researching
these conditions.

The second important point is that these conditions historically
have received very little research attention. In contrast to illnesses
such as cancer and infectious diseases which have been well fund-
ed, well researched, and thus are well understood, our baseline
state of knowledge regarding the physiologic mechanisms and
treatments for these types of conditions is Primitive.

The final important aspect that I would like to highlight is that
it appears as thor the same exact symptom complex can be trig-
gered by many different factors. Most are aware of the debate that
has transpired with Gulf war illnesses with respect to the cause of
these conditions. There appears to be a wide chiasm between two
seemingly disparate views; those on one hand who feel that these
illnesses are triggered by “stress” and those on the other hand who
feel that toxins or infectious agents are involved. The scientific re-
ality is that toxins and infectious agents can act in much the same
way as biologic stressors, as does physical trauma, drugs and emo-
tional stress. Just as there are clearly many different types of such
stressors which are capable of trigge! ring or worsening fibro-
myalgia, chronic fatigue syndrome, and multiple chemical sensitiv-
ity, there are likely to be a plethora of exposures which contribute
to the Gulf war illnesses.

I give this background because the governmental effort to re-
search the causes and treatment of Gulf war illnesses must be
judged in the context of the complexity of the problem. These ill-
nesses are difficult to define and diagnose, have been poorly stud-
ied to date, and are likely to be caused by complex interactions be-
tween an individual and numerous types of stressors they may
have encountered in their environment.

With this in mind, my opinion is that the Government agencies
in general, and the Research Working Group in particular, have
performed very credibly. My sense is that each Government agency

s examined the strengths and weaknesses in these areas and has
promoted internal research in areas of strength, and looked for out-
side expertise and external funding in areas of weakness. This is
a logical approach.

For example, it would be foolish for the CDC, arguably the
world’s finest epidemiologic research organization, to extensively
outsource this type of work. In contrast, the Defense Department
does not have as much internal expertise with these types of ill-
nesses and has been aggressive in funding outside Government, as
well as in stimulating its own researchers in new directions. The
VA has likewise decided to capitalize on its strengths, including
one of the world’s best organizations for performing multicenter
treatment trials. They have asked me and others outside the VA
who have expertise in these illnesses to help work with them and
their internal experts in these illnesses, to design a large treatment


183

My name is Danie! Clauw, and | am an Associate Professor of Medicine and the
Chief of the Division of Rheumatology, Immunology, and Allergy at Georgetown
University Medical Center. | serve as the Principal Investigator of two Department of
Defense grants on Gulf War Ilinesses, and also have funding from the National

Institutes of Health on related matters.

| appreciate the opportunity to give my opinions on the adequacy of the
government efforts to research causes and treatments of Gulf War related illnesses. |
would first like to briefly state my views on the unique problems faced in researching
these illnesses, and then comment on the strengths and weaknesses in the
government research programs. | will conclude by making a few suggestions for how

these efforts might be improved.

As you know, most of the research on Gulf War Illness has focused on the
“unexplained” symptoms and conditions that have affected tens of thousands of
veterans who were deployed to the Persian Gulf during Operations Desert Shield and
Desert Storm. These illnesses are "unexplained" because in these instances we are
not certain of the precise physiologic cause for symptoms such as fatigue, memory
problems, and/or pain in various areas of the body. And in medicine when we do not
know the cause of symptoms, then we likewise struggle with appropriate and effective

treatments.


60

pencil questionnaires as having high levels of psychologic distress.

Besides these two new studies, CDC continues to work with the lowa Department of
Public Health and the University of Iowa to collect additional data to validate health outcomes
reported by participants of the telephone survey component of the Iowa study. Collection of
these data is vital to address the limitations of the self-report telephone information. A follow-up
study focusing on the self-report of asthma symptoms will be conducted with carry over funds
from the original telephone survey.

A sample of 50 Gulf War and 50 non-Gulf War military personnel who completed the

ial telephone survey and met pre-defined criteria for asthma will be invited to participate in
the asthma follow-up study. Additionally, a sample of 100 telephone survey participants who did
not meet criteria for any of the conditions assessed in the survey will be selected from among
persons deployed and not deployed to the Persian Gulf to serve as controls. Subjects will receive
a detailed clinical evaluation which will include physical examination, medical history, tests of
lung functioning, occupational and exposure history, assessment of functional status and quality
of life, assessment of psychiatric history and personality functioning, history of major mental
disorders in first-degree relatives, assessment of social support, and questions about significant
life stressors in the six months prior to the Gulf War. All exams will be conducted at the
University of lowa Hospitals and Clinics in lowa City, lowa. In addition, a review of medical
records for the last 10 years will be completed on a sub-sample of persons who complete the
asthma follow-up study.

Subjects will be classified on the basis of the initial telephone interview as screening

positive or negative for asthma. Subsequent in-person objective testing will classify the


56

further the causes, clinical nature, and public health implications of the higher rates of self-
reported health problems of Gulf War veterans. In this regard, in 1997, NCEH investigators
developed a request for proposals which focused on two programmatic priority areas: (1)
research that enhanced the understanding of conditions and symptoms reported to be more
prevalent among Gulf War veterans, and (2) research that added to the scientific knowledge
needed to develop a research case definition of illness among Gulf War veterans. Specifically,
for programmatic priority area 1, we asked for research on conditions found to be more prevalent
among Gulf War veterans in the Iowa study. We asked that these studies include appropriate
clinical evaluation in order to validate the diagnosis, assessment of the course of the illness
among Gulf War veterans, assessment of risk factors, and assessment of the impact of the illness
on functional status. For programmatic priority area 2, we called for studies focusing on
development of a case-definition for illness among Gulf War veterans. We asked that these
studies evaluate whether symptoms reported among Gulf War veterans represent a unique illness
or are better characterized by existing clinical entities. We also asked for a comparison of data
driven case-definitions and use of known clinical diagnoses in order to determine the best way to
characterize illness among Gulf War veterans or for a validation of previous data driven case
definitions of illnesses among Gulf War veterans.

Eligible applicants included all nonprofit and for-profit organizations. Thus, State and
local health departments, State and local governmental agencies, universities, colleges, research
institutions, hospitals, other public and private non-profit organizations were eligible to apply.

CDC convened a Special Emphasis Panel (SEP) composed of 17 experts from outside

CDC to review and rate the scientific merit of the proposals received. The SEP was


18

We anticipate that the participating medical centers will enroll patients, spouses,
and children by May 1, 1998. We are allowing 18 months for completion of all medical
evaluations.

From 1994 to the present the RWG has worked to coordinate and direct a diverse
research portfolio consisting of 121 projects and a total investment of approximately $115
million. Of these 121 projects, 39 have been completed, 78 are ongoing, and 4 have been
newly awarded and are awaiting startup. Additional research projects are at various stages
of planning. There are 14 identified research focus areas ranging from the effects of
service in the Gulf War on the brain and nervous system to the potential health
consequences of low-level exposure to chemical warfare agents. Approximately one-third
of the projects are epidemiological, one-third are clinical, and one-third are basic research.

This research program, as well as research outside of the government, has yielded
important new information. Some of the highlights of recent research findings include:

«Population-based epidemiological studies are showing that Gulf War veterans

self-report more symptoms and exposures than non-deployed veterans of the
same era. Currently it is not possible to identify a causal connection between
the reported symptoms and exposures. However, ongoing and newly funded
projects are directed toward determining whether such a connection may exist.
© Based on VA and DoD mortality studies there does not appear to be more
deaths from disease-related causes among Gulf War veterans when compared
to non-deployed veterans of the same era. VA plans to continue following the

mortality experience of Gulf War veterans well into the future.

12


47

investigator would like a copy of the Human Use Protocol Review Checklist. Inquiries may be
forwarded in writing to

Commander

USS. Army Medical Research and Materiel Command
ATTN: MCMR-RCQ

Fort Detrick

Frederick, MD 21702-5012

or by TELEFAX (301) 619-7803

38


51

among Gulf war veterans. Specifics regarding these two studies are
detailed in my written testimony.

Besides these two new studies, CDC continues to work with the
Towa Department of Public Health and the University of Iowa to
collect additional data to validate health outcomes reported by par-
ticipants of the Iowa study. A followup study focusing on the self-
report of asthma symptoms will be conducted.

The University of Iowa has also been funded by DOD to conduct
additional validation studies on other health outcomes, including
depression, cognitive dysfunction and multisystemic conditions. An
interagency agreement is currently being developed that will en-
able CDC investigators to provide technical assistance to DOD and
the University of Iowa for this study.

Finally, HHS has developed a research strategy for addressin;
health effects of exposure to multiple chemicals. The principal go:
for fiscal year 1998 is to develop a 5-year research plan. is will
include joint sponsorship by CDC and the National Institute for
Environmental Health Sciences of a consensus-building conference.
In addition, HHS will augment funding for an existing NIH grant
announcement calling for research projects on the health effects of
chemical mixture exposures.

Together with research sponsored by VA and DOD, HHS’s past
research efforts have added new or confirming information to the
growing knowledge base managed by the Research Working Group.
Our new research activities will continue to contribute to a better
understanding of illnesses among Gulf war veterans and will assist
in providing new information to guide the collaborative planning
process of the Federal Government.

HHS is proud to serve along, with the other two principally re-
sponsible de rtments on the Persian Gulf Veterans’ Coordinating
Board. This board has provided a necessary forum for the exchange
of information within the Government and for the development of
interdepartmental relationships, which have fostered greater un-
derstanding and cooperation. We look forward to continuing col-
laboration of this type.

That concludes my statement.

Mr. Towns. Thank you very much, Dr. Barrett.

[The prepared statement of Ms. Barrett follows:]


2

2. The Government's duty to take all reasonable precautions
to preserve the fighting force must include recognition of the
startling proliferation of chemical and biological weapons among
potential adversaries and terrorist organizations and an
obligation to implement the best possible medical
countermeasures.

In a recent report on the proliferation of weapons of mass
destruction, Secretary Perry wrote:

We received a wake-up call with Saddam Hussein's use of
SCUD missiles during Operation Desert Storm and new
information on his ambitious nuclear, biological, and
chemical weapons programs. The proliferation of these
horrific weapons presents a grave and urgent risk to the
United States and our citizens, allies, and troops abroad.
Reducing this risk is an absolute priority of the United
States.

ae

. . .. The bad news is that in this era the simple
threat of retaliation that worked during the Cold War may
not be enough to deter terrorists or aggressive regimes from
using nuclear, biological, and chemical weapons. . . . The
bottom line is that, unlike during the Cold War, those who
possess nuclear, biological and chemical weapons may
actually come to use them. The increase in the likelihood
of regional war in today’s world raises the risk.

This new danger requires new thinking and new
leadership on how to prevent, deter and, if necessary,
respond to the threat. :

This Report goes on to document very aggressive chemical and
biological weapons programs in North Korea, China, Iran, Iraq,
Libya, Russia, and possibly other countries. In addition, there
have been warning signs regarding activities of terrorists and
insurgents, including the 1995 nerve gas attack in Japan. The

1 "Proliferation: Threat and Response," Office of the
Secretary of Defense, April 1996.


142

Ms. NEWTON. It is outside the purview of my institute. I would
have to get the—

Mr. SHAYS. Do you have any background?

Ms. NEWTON. My degree is in biochemistry, but in my institute
we work on chemical exposures, not biological.

Ms. BarRETT. I have no background on that. I would like to add
some information regarding——

Mr. SHays. Sure. I am sorry, I should have asked both of you.
Let me ask both of you in terms of detection of chemical exposure.
I apologize.

Ms. BARRETT. There was CDC involvement early on. At the time,
the exposure of concern was oil well-fire smoke, and there was very
early involvement of sending a group of scientists over and doing
measurements of volatile organic compounds, both in the theater of
operations and from the base camp. I think CDC also has quite a
bit of expertise in doing measurement of chemical exposures and
looking at biomeasurement, biomarkers.

Mr. Suays. So do you concur with the answer, though, that some
chemicals cannot be easily detected even after acute exposure and
that some can, and that over time it is very difficult to get any de-
tection?

Ms. BARRETT. Yes, I agree with that. I think it also points to the
importance of trying to develop better biomarkers. I know our lab
is very involved in this issue and is very interested in trying to de-
velop a rapid assessment battery that could be used for future de-
ployments, where you could have immediate assessment of whether
troops were exposed to chemicals and get a very rapid turnaround
on, you know, up to 150 different types of chemicals.

Mr. Suays. You all are under oath, and I only say this because
I am going to ask a question that I want you to really think about
before you answer.

There have been studies of the viability of our masks. Are any
of you aware—I don’t want you to go into them, because they are
classified. But have any of you heard or read any reports on the
viability of our masks? I would ask each of you.

Dr. FEUSSNER. No, sir.

Mr. Suays. OK.

Mr. GeErRITY. No.

Ms. WINEGAR. Yes.

Mr, SHays. OK.

Ms. BARRETT. No.

Ms. NEWTON. No.

Mr. SHays. Doctor, don’t you think it is important that—excuse
me. Dr. Winegar, don’t you think it is important that others that
have to deal with this issue should know about these studies? Do
you think that these studies should be made available to the VA?

Ms. WINEGAR. I certainly think that the relevant information
that is needed regarding possible failures of masks which would
lead to subsequent exposure is something that is generally known.
It is not only the intactness——

Mr. SHays. What is generally known?

Ms. WINEGAR. That sometimes the masks don’t fit perfectly, and
that therefore they could leak.


135

Mr. SANDERS. Right, exactly.

Dr. FEUSSNER. And so that a physician, for example, who might
believe that this antibiotic could alleviate these symptoms or cure
this disease is in a position to prescribe those antibiotics.

Mr. SANDERS. And how many doctors in the VA system are doing
that right now?

Dr. FEussNER. I don’t know the answer to that.

Mr. SANDERS. I believe none. And it is not as easy as you think,
because there is no presumption that is not yet VA approved.

I mean, if this were stress, for example, you were operating
under the assumption of stress, you would not use antibiotics in
that sense, would you?

Dr. FEUSSNER. Well, the antibiotic treatment is a potential thera-
peutic avenue. The antibiotics are not harmless, and difficulties
with chronic antibiotic therapy such as modification of the gut
flora, precipitation of persistent diarrhea, adverse drug effects,
superinfection with other fungal infections, et cetera, are credible
risks.

Mr. SANDERS. But don’t you think that if veterans understood
the risk and you explained it, as you just did right now and said,
look, we are not guaranteeing anything; there is a chance, in fact,
that you may have a problemn——

Dr. FeussNeRr. I think the veterans could make an informed deci-
sion about whether to participate in a study or not.

Mr. SANDERS. Now the question is, so we don’t discuss this 5
years from now again and go through all of this stuff again, when
are you going to allow veterans that choice?

In my State of Vermont, I am here to tell you, many of these
guys would like that.

Will you come to the State of Vermont and start a controlled ex-
periment so we can learn something? Yes?

Dr. FEuSSNER. I will try to start an experimental trial of anti-
biotic therapies, yes.

Mr. SANDERS. OK. We will be in touch with you, and Dr. Victor
Gordon, whom you may know, who is one of the better physicians
in the VA system, valiantly trying to do this, will be delighted to
work with you. He is from Manchester, NH. I think I can speak
for Dr. Gordon in that respect.

That’s No. 1. I am glad to hear that and I will be in touch with
you.

The No. 2 question I would like to raise to you, in our report we
heard—and again, we are not scientists here, so I am not saying
the people are right or whether they are wrong, but I want you to
comment. OK?

We heard from a gentlemah named Dr. Thomas Tiedt, T-I-E-D-
T, a neuroscientist and former pharmaceutical industry researcher,
and this is what he told us. He told us some scary stuff. This was
his opinion.

He said—he worked at the University of Maryland on
Pyridostigmine bromide. He is an expert, and this is what he said.

le said, “Our work was followed by an explosion of research by
DOD during the 1980’s, the most relevant of which was produced
by my co-authors,” et cetera, and this is what they concluded.
“BOD research established by the early 1980’s that PB would be


18

effects of low-level exposure to nerve agents dating back to the 1950s. The MFUA

informed us that such a project

indeed feasible and they are currently preparing a full
proposal for review.

Also in early 1997, the RWG established a small subgroup of experts on the health
effects of nerve agents to develop a broad-based research strategy for investigation of the
long-term health effects of low-level exposure to chemical warfare nerve agents. This
plan will be published in an upcoming Annual Report to Congress on Gulf War veterans’
illnesses research.

‘The sarin terrorist attacks in Japan provided an opportunity to study the health
consequences of a real-life confirmed sarin exposure. A VA researcher, who is also the
Director of the VA Boston Environmental Hazards Research Center, has been.
collaborating with Japanese investigators who have conducted follow-up studies on 18
exposed individuals. These subjects experienced acute (i.e. sudden onset), but mild,
symptoms arising from the Tokyo subway sarin attack of 1995. Investigators have studied
psychological, neurobehavioral, and neurophysiological outcomes in these subjects using
up-to-date techniques. The outcome measures in each of the exposed subjects have been
compared with matched non-exposed control subjects. Three papers resulting from this
research have been recently published in the scientific peer-reviewed literature. These
papers provide new insight into the effects of clinical exposures to sarin 6-8 months
following the attack. In comparison with matched controls, the exposed subjects
manifested subtle neurophysiological effects that, although they were not clinically
significant, do show that sarin can cause effects on the brain some time following recovery

from the acute effects.


137

There is research being done by a number of people, including
Dr. Claudia Miller of the University of Texas, Southwest Medical
Center, who testified before this committee; and basically what she
said, relevant to the chairman’s discussion a little while ago, is that
many of the symptoms that she is seeing in Gulf war patients are
precisely the same symptoms that she saw among workers who
were exposed to heavy doses of pesticides or other organo-
phosphates, and she believes there is a connection between the two.
But she believes in the issue of multiple chemical sensitivity.

And she says, she—let me read from the report. She testified
that common symptoms reported by these patients at the time they
were exposed were often flu-like illnesses—fatigue, concentration
difficulties, headaches, shortness of death, musculoskeletal pain
and gastrointestinal symptoms. She saw the same problems be-
tween people in the civilian sector and Gulf war veterans.

What conclusion do you reach? Do you agree with that?

Dr. FEUSSNER. Well, I think that there are several possible ex-
planations for these exposures. I think you mentioned organo-
phosphate pesticides. Earlier in these hearings we have talked
about chronic fatigue syndrome, we talked about fibromyalgia, and
we have talked about exposure to multiple chemicals, and I think
those are all potential exposures that are causing symptoms in our
patients.

Mr. SANDERS. OK. Dr. Feussner, before we leave today, I will get
your card, I will call you up, and I will work with you to develop
a treatment protocol.

Dr. FEUSSNER. The antibiotic arm.

Mr. SANDERS. OK?

Dr. FEUSSNER. Yes, sir.

Mr. Suays. I wouldn’t wish that on my worst enemy.

Dr. FEUSSNER. Well, he is not suggesting that he is going to plan
the trial, just to facilitate.

Mr. SHays. That’s for sure.

Mr. SANDERS. Thank you. Thank you, Mr. Chairman.

Mr. SHays. I would like to ask each of you, to the extent that
you would be able to answer this question, whether we have any
known way of detecting chemical exposure. I will start with you,
Dr. Winegar, and just go right down the list. Thank you.

Ms. Winecar. Yes, we do have ways of detecting chemical expo-
sure, but before I go further, I do want to clarify the interchanging
of the word “chemicals” and the DOD’s perhaps limited context of
chemical warfare agents, and those are not necessarily the same.
And I think that in some of the questions and answers, we may
have misconstrued what the context of the question was.

When you were referring earlier to Dr. Joseph’s quotation and
asking me whether I believe that low-level exposure to chemicals
could lead to serious illness or death, I believe that his statement
was made in the context of the known chemical warfare agents——

Mr. SHAYS. No, no, no, no, no. Just a basic question about chemi-
cals.

Ms. WINEGAR. Well, then my answer—that was how I interpreted
the question.

Mr. SHays. So how would you have answered the question?


55

to assess the prevalence of illnesses among Gulf War veterans from Iowa. The Pennsylvania Air
National Guard Study was conducted in response to a request by the Department of Veterans
Affairs in conjunction with DoD, and the Pennsylvania Department of Health to investigate a
reported cluster of illnesses among members of a specific Air National Guard unit. More
recently, NCEH directly provided funding to expand on the findings of the Iowa and
Pennsylvania studies

The Iowa study was one of the first population-based epidemiologic studies to document
that Gulf War veterans are reporting more medical and psychiatric conditions than their
nondeployed military peers. The study, conducted in collaboration with the lowa Department of
Public Health and the University of Iowa, identified several medical and psychiatric conditions
that need to be studied in more detail. These conditions include fibromyalgia, cognitive
dysfunction, depression, chronic fatigue, post-traumatic stress disorder, and respiratory illness
(asthma and bronchitis). The conditions identified in this study appear.to have had a measurable
impact on the functional activity and daily lives of these Gulf War veterans. However, these
conditions may not be unique to Gulf War veterans and may be similar to the experience of
veterans in other wars.

Dr. William Reeves will be providing you with information regarding the Pennsylvania
study. But briefly, the results of this study found that Gulf War Veterans were more likely to
report a variety of symptoms including fatigue, diarrhea, joint pain, nasal or sinus congestion,
muscle pain and memory difficulty. This investigation also addressed the development of a
research case definition for illness among the Gulf War veterans studied.

‘The results of the fowa and Pennsylvania studies established the need to investigate


2

Without that focus, without the discipline to ignore the deaden-
ing demands of institutional traditions and predispositions, we risk
studying Gulf war veterans, literally, to death.

In looking for a sharper focus and a greater sense of urgency in
Federal research, we are mindful of the incremental nature of the
scientific inquiry. We share the inevitable frustration of research-
ers and patients as nature slowly yields her secrets. Many sick
Gulf war veterans present complex, difficult to diagnose symptoms
and disease states. Research into similar symptomatically de-
scribed illnesses in the civilian population—fibromyalgia, chronic
fatigue syndrome, multiple chemical sensitivity—appears as frag-
mented and inconclusive as Gulf war studies to date. But we are
convinced the very intractability of the problem justifies, even de-
mands, a more keenly concentrated approach.

For sick Gulf war veterans, the question is why private research-
ers appear to be making better progress than their Government in
defining, and therefore understanding, their illnesses. They ask
why studies are just beginning on wartime chemical exposures
known to produce health effects at low levels in industrial settings.
They ask why the starting point for so much research is psycho-
logical theory, stress, when their symptoms and pain are intensely
physical.

‘o help answer these questions, we will hear testimony from
members of the Research Working Group, the General Accounting
Office, and researchers who have submitted proposals for evalua-
tion and funding. We appreciate their time and expertise, and we
truly look forward to their testimony.

Again, I would like to welcome our guests, those from the VA
and the DOD and HHS as well as private researchers, and thank
them all for being here.

At this time I would recognize my partner, Mr. Towns.

Mr. Towns. Thank you very much, Mr. Chairman. Let me begin
by saying I really, really appreciate the work that you have done
in this area. You have re: been involved, and I thank you and
the staff for bringing us to this point in time. I think this is a very
important hearing, and I again thank you.

Mr. Chairman, I want to also say to you that I think that we
need to move in a very aggressive kind of way to make certain that
the research that needs to be done is done. Anyone who follows this
issue knows that this subcommittee’s hearings and reports have led
the way in examining the illnesses experienced by Persian Gulf
war veterans.

Throughout this process, our ultimate goal has been to assure
that veterans receive appropriate medical care at VA clinics and
hospitals. Appropriate care requires effective treatment and com-
petent practitioners. However, both the efficacy of the treatment
and the capability of the professionals are jeopardized by ineffec-
tive or inappropriate research. Without proper research concerning
the cause of illnesses and development of medicines to treat the
disease, the practitioners and patients are left with few options and
many frustrations.

Therefore, we are here today to assure that serious and substan-
tial medical research is done to address the health problems faced
by the Persian Gulf war veterans.


174

protected by the honored peer review process, although I am not
sure what to do instead of that.

Finally, now, with all the talk about a case definition, there are
people coming forth that are going to talk the case definition talk,

ut they are going to talk, instead of a case definition of the Gulf
war illness which includes symptoms that are very unique to Gulf
war veterans, they are going to tell you about the case definition
of chronic fatigue syndrome, multiple chemical sensitivity, and
fibromyalgia. se are things that occur in the civilian population
that have similarities to Gulf war syndrome, but are not the same.
If we use those case definitions not developed in Gulf war syn-
drome, what you are going to find is yes, you are going to have
some sick Gulf war veterans in there, but you are going to have
a lot of Gulf war veterans that are going to have other things. You
will water down the studies and not find anything.

My conclusion is that I think what has happened is there was
a strong belief early throughout the government, throughout the
population, that this was not real. I think that is a self-fulfilling
prophecy, and through conservation of belief we have filtered out
any evidence to the contrary, and I am very pessimistic that that
can be fixed.

[The prepared statement of Dr. Haley follows:]


198

Dr. CLAUW. But it’s the body’s response to—the body can only re-
spond in a certain number of ways to different types of things. The
nervous system, the hypothalamus, pituitary gland, there are dif-
ferent things that effect a stereotypical response, that will be the
same to sarin as it will be to emotional stress, as it will be to an
infection. It appears as though these types of illnesses are capable
of being triggered by a whole host of different things again that I
would view as “stressors.”

Mr. SANDERS. If I may, I agree with everything you are saying,
but doesn’t that make the word “stress” a meaningless word?

Dr. CLauw. It is a terrible word.

Mr. SANDERS. You go to 899 people and you say, what is stress?
There’s—you know, there is an emotional reaction, we are nervous,
afraid. You are suggesting oh, sarin, bring forth a reaction. No one
normally would think that sarin’s effect on the body is the same
as an emotional.

Dr. CLauw. I guess I would say, though, that biologists and phy-
sicians and scientists view stress in the latter way rather than the
former. You are talking about 99 lay people. I wish we had a dif-
ferent word that we could use for it, because it really causes a
great deal of problem. It is as huge an emotional issue with
fibromyalgia and chronic fatigue syndrome, multiple chemical sen-
sitivity, as it is with Gulf war illness, and I 1! we need to get
past this. I think it is too divisive.

Mr. CHAN. Can I add a little to this?

Mr. SHays. You may. I just want to—Dr. Reeves, I just want to
make sure that I am getting your attention here in terms of wheth-
er you agree, or want to choose to point out any area where you
would amplify or disagree with the earlier panel or the present dis-
cussion with this panel.

Dr. REEVES. I think there is a couple of caveats that I would
make. I think one is that there is a very clear—and it is almost
impossible to prevent—a level of misunderstanding between tech-
nical issues and nontechnical issues, the concept of stress being
when one gets dengue fever, the virus is gone in 3 days and you
are on your back for a half a year, and it is because of the stress
of that infection.

When you are a prisoner of war, you have a chronic stress which
may be an emotional stress, a physical stress, and there are prob-
lems in probably the public opinion understanding of these and the
scientific. It is the same problem that came up with the wording
of a hypothesis that serious scientists approach things in a very
set, scientific fashion and this is often misunderstood by the gen-

eral public.

ee the major problems in the area, I think for me, from a
public health point of view, we have a large number of veterans
who are currently not well, who need treatment. They need care-
fully considered treatment trials, not willy nilly treatment trials in
which we can do more harm than we do food. I think that is very
important. I think anything we treat with is not necessarily—not
causing separate illnesses. We do not want to get into the same
problems using antibiotics, et cetera, that we did using the PB. The
argument goes both ways.


163

warfare agents) were inadequate. Second, the veterans were
typically exposed to a wide array of agents with commonly accepted
health effects, making it difficult to isolate and characterize the
effects of individual factors or to study their combined effects.
Third, the passage of time following these exposures has made it
increasingly difficult to have confidence in any information

gathered through retrospective questioning of veterans.”

In part, the latter difficulty was created by the delayed release
of information about detection of chemical warfare agents during
the war as well as the delayed collection of exposure data. Five
years passed before DOD acknowledged that American soldiers may
have been exposed to chemical warfare agents shortly after the war
ended in 1991 (at the Khamisiyah site). Moreover, although
chemical detections by Czech forces are regarded as valid by DOD,
the origin of the detected chemical agents has not been identified

by either DOD or CIA. In the face of denials by DOD officials,

Large numbers of veterans questioned during their participation in
the VA's health registry examination program reported they did not
know whether they were exposed to certain agents. “Don't know"
responses were greatest for nerve gas (64.9 percent), mustard gas
(60.2 percent), depleted uranium (52.5 percent), chemical-agent
resistant coating (47.8 percent), microwaves (32.8 percent), paints
or solvents (24.9 percent), and pyridostigmine (21.1 percent). To
the extent that a response of some kind reflects greater certainty,
veterans were more confident in their reports regarding smoke from
tent heaters, passive smoking, diesel or other petrochemical fumes,
skin exposure to fuel, pesticides in cream or spray form, and
burning trash or feces, each of which resulted in fewer than 11
percent of respondents reporting "don't know." While such
confidence does not necessarily mean that the reports are accurate,
the lack of confidence in responding to questions about some
exposures raises questions about studies relying on self-reports to
assess these exposures.

15


72

It is unclear what “anticipatory consent” means. For example, is it a subset of
option 2 or option 3, as described in the comment to the previous question? The
primary issue is not the proximity of the consent to the use of the drug or vaccine, but
whether the military command authority can order military personnel to use a drug or
vaccine under the extremely limited circumstances described in the comment to
question 2, above, and covered by the current military combat exigency rule. If the
concept of “anticipatory consent" means providing information and training to military
personnel in advance of contingency operations, this is very desirable.

A.(5) Instead of waiving the requirement for informed consent, is it feasible to
obtain anticipatory consent from military recruits (prior to their recruitment into the
military) for the future use of investigational products during a military conflict? If it
is feasible, would such consent be valid? What would be the needed consent algorithm
to make it valid and feasible?

Again, the meaning of "anticipatory consent" is not clear. In a very real sense,
under the all-volunteer military force, the act of volunteering for military service is
consent to be subject to command authority for the conduct of military operations. It is
well understood that this command authority can order an individual to do things that
may result in the loss of the individual's life. It is also well understood that the
autonomy enjoyed by civilians in American society is significantly sacrificed in the
specialized society of the military. To the extent the conduct of military operations
includes requirements to take drugs or vaccines when indicated by the best evidence of
safety and efficacy, the degree of peril posed, and the absence of a satisfactory
alternative therapy (whether or not those products have been approved for general
commercial marketing in the United States), this is subsumed by the obligation freely
accepted — legally, ethically, and practically — by every military member.

Tf the point of the question is whether informed consent similar to that under 21
CFR Part 50 is feasible, the answer is that it is not. Among the reasons is that the
regulations disallow any penalty for declining to use an IND product, as well as assure
the right to withdraw consent at any time. If declining means the individual who wants
to join the military will not be accepted, the "voluntariness" of the consent will not
meet the regulatory requirement, nor would irrevocable consent. In addition,
providing detailed information regarding a variety of possible threats and medical.
countermeasures a recruit might face during a period of military service is not feasible.

A.(6) If the interim rule is needed, are there changes that should be made to it
based on experiences during and following the Gulf War? If so, what are these
changes and why should they be made.

The Department of Defense has no changes to recommend based on experiences
during and following the Gulf War, but welcomes the opportunity to consider changes
suggested in the public comment process.

A.(7) Can or should the interim rule be narrowed in scope? If so, how?


27

programmnatic relevance of research proposals that have been competitively and scientifically peer-
reviewed

The guiding RWG goals for GWVI research are to: seek the causes (pathogenesis) of the
unexplained illnesses of Guli War veterans, use new knowledge of basic mechanisms to help
veterans, and avoid or reduce such unexplained illnesses in future military deployments. Areas of
medical research focus include assessing:

© environmental chemicals, prophylactic drugs, and military materiel for synergistic toxic
interactions;

«the effect of exposure to subclinical levels of chemical warfare agents on long-term health
consequences; and

‘the confluence of cognitive, emotional and physical factors that produce chronic,
nonspecific symptoms and physiological outcomes typical of the undiagnosed illnesses of
some veterans of the Gulf War.

Other areas of medical research pursuit or interest include those on stress, reproductive
outcomes, infectious diseases including mycoplasma and leishmaniasis, multiple chemical
sensitivity, chronic fatigue syndrome, fibromyalgia, and epidemiological studies.

Research Operations

The Department of Defense uses competitive procedures to solicit extramural proposals for
scientific studies and research on GWVI. This extramural research program is administered for
the DoD by the U.S. Army Medical Research and Materiel Command (USAMRMC), Fort
Detrick, Maryland. This Command was selected because its Headquarters staff and contracting
activity, the U.S. Army Medical Research Acquisition Activity (USAMRAA), have a long history
of providing responsive program execution support to the DoD on a broad spectrum of
Congressional special interest, medical and biomedical science and technology programs. They
possess unparalleled experience and have in place the contract clauses and review processes
necessary for:

solicitation and selection of fully qualified proposals on merit factors of program
relevance and scientific excellence;

«resolving complex and difficult issues of regulatory compliance (e.g., protection of human
research subjects, ensuring welfare of research animals, safe use of high hazard etiologic
agents, research safety and surety for handling highly toxic chemical warfare agent
materials); and

* rapid program starts through application of streamlined extramural research acquisition
processes.

Solicitation. Research proposals are solicited through the use of either an open-ended Broad
‘Agency Announcement (BAA) or through a BAA announcing specific research opportunities.
These announcements are formally made through publication in the Commerce Business Daily
and may be accessed and downloaded from the Internet (http://www-usamraa.army.mil/baa.htm).


10

Department of Defense Comments
on FDA Questions Regarding Interim Final Rule

Issue A: Questions regarding the interim rule.
A.(1) Should the agency revoke the interim rule? If so, why?

The Department of Defense considers it a national defense requirement that the
authority of the military combat exigency rule be maintained.

A.(2) Are there circumstances under which use of the interim rule would be
justified? If so, what are those circumstances?

The circumstances under which use of the military combat exigencies rule is
both justified and required are that based on the best evidence of safety and efficacy of
a drug or vaccine, the degree of peril posed by the threat for which the drug or vaccine
is indicated, and the absence of a satisfactory alternative therapy, failure to use the
drug or vaccine will, regardless of the personal preferences of the military member, be
contrary to the best interests of the member, endanger other personnel in the unit, and
tisk failure of the military mission.

Implicit in this answer are three points which, at the risk of redundancy, bear
explicit underscoring. First, the military purpose is force protection, not data
collection. Stated another way, it is medical treatment, not medical research. Second,
the drugs and vaccines involved will be safe. The evidence of safety will be
comparable to that for drugs and vaccines approved by FDA for general commercial
marketing. They are not exotic, experimental drugs. Third, the reason these products
are classified as “investigational new drugs" — i.e., the reason they have not been
approved by FDA for general commercial marketing — is that efficacy has not been
proven in controlled human clinical trials, which is the normal FDA standard for drug
approvals. But apparent efficacy will be established by results of animal trials and
other means. Stacked against the degree of peril and absence of an alternative, the
evidence of safety and efficacy — even if less than that necessary for FDA approval for
general commercial marketing throughout the United States — is sufficient for FDA
approval for standardized use in the military combat exigency.

A.(3) The interim rule is based on the premise that informed consent is not
Feasible in military combat exigencies because if a soldier were permitted to say “no,”
this could jeopardize the individual soldier's life, endanger other personnel in his or
her unit, and jeopardize the accomplishment of the combat mission. DoD has alleged
that it is not an option to excuse a nonconsenting soldier from a military mission.
Given the experience in the Gulf War, does this rationale still hold?

The use of the military combat exigencies rule during the Gulf War was to help
protect American military personnel from the enemy's horrific arsenal of chemical and


146

STATEMENTS OF DONNA HEIVILIN, PH.D., DIRECTOR, PLAN-
NING AND REPORTING, GENERAL ACCOUNTING OFFICE, AC-
COMPANIED BY KWAI-CHEUNG CHAN, DIRECTOR, SPECIAL
STUDIES AND EVALUATION, GENERAL ACCOUNTING OF-
FICE, AND SUSHIL SHARMA, PH.D., ASSISTANT DIRECTOR,
SPECIAL STUDIES AND EVALUATION, GENERAL ACCOUNT-
ING OFFICE; ROBERT HALEY, M.D., DIRECTOR, EPIDEMIOL-
OGY AND SCIENTIFIC GRAPHICS LABORATORY, UNIVERSITY
OF TEXAS SOUTHWESTERN MEDICAL CENTER; DANIEL
CLAUW, M.D., CHIEF OF RHEUMATOLOGY, GEORGETOWN
UNIVERSITY SCHOOL OF MEDICINE; AND WILLIAM REEVES,
M.D., BRANCH CHIEF, VIRAL EXANTHEMS, CENTER FOR DIS-
EASE CONTROL AND PREVENTION

Ms. HEIVILIN. Mr. Chairman, members of the subcommittee, I
am pleased to be here to discuss GAO’s evaluation of the Federal
strategy to research Gulf war illnesses. We reported our findings
on this strategy in June 1997 as part of our response to a congres-
sional mandate. However, before I discuss our findings, I would
like to provide a little background information.

The United States troops were reportedly exposed before, during,
and after the Gulf war to a variety of risk factors. The Federal
Government, primarily through DOD and VA, has sponsored a va-
riety of research on the Gulf war veterans’ illnesses.

Most of the research sponsored by the Federal Government is
characterized as epidemiological. The objectives of epidemiologic re-
search are to determine the extent of the disease and illnesses in
the populations and subpopulations, the causes of the disease and
its modes of transmission, the natural history of the disease, and
the basis for developing preventive strategies or interventions.

I would like to point out that epidemiological research is a useful
tool for determining the cause of illness and effective treatment.
However, to conduct such research, investigators must follow three
principles: first, they must specify diagnostic criteria which can be
used to reliably determine who has the disease or condition being
studied and who does not, and select appropriate controls; that is,
people who do not have the disease or condition, for comparative
purposes.

Second, the investigators must have valid and reliable methods
of collecting data on the past exposures of those in the study, and

ssible factors that may have caused the symptoms. It is particu-
larly critical when studying low-level or intermittent exposure to
drugs or chemicals to be able to obtain dose-specific exposure infor-
mation as well as data on the intensity and duration of the expo-
sure, and it is difficult to detect any effects of the exposure when
the type, amount, and extent of the exposure of individuals is re-
ported incorrectly.

Third, it is important that a sufficient number of persons be
studied to have a reasonable likelihood of detecting any relation-
ship between exposures and disease.

I would like to turn to our findings at this point, and I have five
that I want to report. First, the Government was not proactive in
researching Gulf war illnesses. Although the veterans’ health prob-
lems began to surface in the early 1990's, the vast majority of the
research was not initiated until 1994 or later, and much of it re-


63

mechanisms of action as they relate to human health.

Together with research sponsored by VA and DoD, HHS’s past research efforts on the
health effects of Gulf War service have added new or confirming information to the growing
knowledge base managed by the Research Working. Our new research activities will continue to
contribute to a better understanding of illnesses among Gulf War veterans and will assist in
providing new information to guide the collaborative planning process of the Federal
government. HHS is proud to serve along with the other two principally responsible
Departments on the Persian Gulf Veterans Coordinating Board. This Board has provided a
necessary forum for the exchange of information within the government and for the development
of interdepartmental relationships, which have fostered greater understanding and cooperation.
We look forward to continuing collaboration of this type, not only for addressing the important
concerns of Gulf War veterans, but also for helping to properly prepare the Nation for future

conflicts and peacekeeping missions.


20

* Neurobehavioral studies of Gulf War veterans and control populations suggest
that Gulf War veterans have some brain function abnormalities in such areas as
memory, cognition, and motor control in comparison to non-deployed era
veterans. Some of these deficits can be accounted for by psychological factors.

© Two different research groups have independently found that health symptoms
in Gulf War veterans may be associated with PTSD symptoms.

© A study conducted at the National Cancer Institute examined blood samples
drawn from deployed veterans who went to the Gulf immediately after the end
of hostilities. Blood samples were.collected in Germany and in the Gulf and
tested for a marker of exposure to polycyclic aromatic hydrocarbons (a
carcinogenic product of partial combustion of petroleum products). The
researchers found more markers for PAH exposure in the samples taken in
Germany than in the Gulf.

As the research programs of the federal government continue to provide more

results, we will substantially increase our understanding of Gulf War veterans’ illnesses,

which will, in tum, enhance our ability to diagnose and treat them. In addition, this newly

gained knowledge will enhance prevention and intervention of illnesses in participants of

future deployments.

Twill conclude my testimony here and answer any questions you may have.


37

ATTACHMENT 2
FACILITY SAFETY PLAN (FSP)?

Laboratory research may pose special risks to the safety and health of personnel and to the
environment. Law and USAMRMC policies governing workplace safety and occupational health
(analogous to Federal and state regulations) require that research be conducted safely and in an
environmentally responsible manner. Offerors notified that their proposal is being considered for
award shall provide the information identified below, as applicable to the type of research
proposed, either in the form of existing organizational documentation or by preparation of a
Facility Safety Plan addressing each of these points.

1. Facility Description:

a. Describe the facility where work will be performed (e.g., engineering controls and
relevant building/laboratory ventilation features, special containment features, fire
suppression systems, etc.)

b. Describe the surrounding environment (e.g., urban, rural, single or mixed-use building,
number of employees, size of adjacent populations, etc.).

2. Safety and Occupational Health Programs:

‘a. Describe the organizational safety program, to include inspections, standing operating
procedures, personal protective equipment, and safety committees, and identify the
document(s) that codify the program. Describe discrete program elements such as
biological, chemical and radiation safety programs

b. Identify existing Federal, state or local documents, permits, or certifications (e.g.,
building use permits, hazardous materials use permit, JCAHO, GLP, etc.) that relate to the
proposed research or facilities proposed for use.

c. Describe the safety program for use of hazardous materials (e.g. HAZCOM,
Laboratory Standards (29 CFR 1910,1450), permitting, internal regulations, etc) by which
compliance with Federal, state and local regulations pertaining to hazardous materials
transportation, handling, storage, and disposal is accomplished.

d. Provide a complete listing of all hazardous, radioactive, chemical, and/or biological
substances to be used in the conduct of the proposed research. Proposals to use these
materials must include, as a minimum, an organizational license or approval (e.g. Nuclear
Regulatory Commission for use of radioactive materials) and approval by the
organizational committee for the PI to use material in the proposed manner (e.g.,
Radiation Protection Committee, Institutional Biosafety Committee, etc.).

2 From U.S. Army Medical Research and Materiel Command Broad Agency Announcement 95-1

Bl


157

factor funded for the greatest fraction of total - 32 studies (30

percent) .**

While research on exposures to stress réceived early emphasis,
other hypotheses have received scant support. In its Final Report,
the Institute of Medicine discusses the evidence for a number of
disease hypotheses, including multiple chemical sensitivity,
fibromyalgia, and organophosphate-induced delayed neuropathy.
However, the federal research program has supported only one study
of the relationship between symptoms reported by veterans and
fibromyalgia. In addition, prior to October 1996, only one of the
studies initiated in response to Gulf War veterans’ illnesses
focused on the health effects of potential exposures to chemical
warfare agents.’ While multiple studies of the role of stress in
the veterans’ illnesses have been supported with federal research
dollars, other hypotheses have been pursued largely outside the

federal research program.

Although veterans raised concerns about potential chemical
exposures soon after the war, the federal research plan was not

modified to include an investigation of these concerns until 1996,

‘presidential Advisory Committee on Gulf War Veterans’ Illnesses,
Final Report, p. 34 (Washington D.C.:GPO), December 1996.

*This study of the impacts of sulfur mustard agent is a
collaborative effort between the Portland VA Medical Center and the
Oregon Health Sciences University. The principal investigator for
the study pointed out that the possibility of chemical warfare
exposure seemed plausible even in 1994 when he sought initial
funding for this research.


57

composed of federal, state, and private members with expertise in public health issues,
epidemiology, environmental and occupational medicine, research methodology, and Gulf
War health issues. In addition, representatives from two national Veterans’ Service
Organizations served as members on this panel. Members were also selected in order to ensure
adequate geographic, racial, and gender diversity. SEP members were provided with clear
ctiteria for evaluating the proposals (these criteria were also included in the request for
proposals). These criteria including ratings of the significance, originality, and adequacy of the
proposed research plan; the inclusion of clear, measurable objectives; the adequacy of the
proposed evaluation plan; and the degree of the investigators’ understanding of the problem and
ability to conduct the proposed work.

In addition to the review by the SEP, as described above, a subcommittee of the Research
Working Group, composed of representatives from DoD, VA, and HHS, reviewed proposal
abstracts and summary statements from the SEP review. All abstracts and summary statements
were redacted so that the Research Working Group subcommittee was blinded to the institutions
and investigators associated with each proposal. The subcommittee was asked to review the
proposals for relevancy to the research goals identified by the Research Working Group. The
subcommittee’s recommendations corresponded with the scientific merit scores.

Based on the results of the SEP and Research Working Group reviews, two new studies
were selected for funding, one study addressing each of the programmatic priority areas. Both of
these studies were funded at $600,000 per year for a three year period.

‘Addressing priority area 1, Dr. David Ozonoff of the Boston University School of Public

Health will conduct a study entitled “Cognitive Function and Symptom Patterns in Persian Gulf

6


23

ordinate Federal research into the health consequences of service
in the Persian Gulf war. The genuine concern and recognition of
the magnitude and consequences of the challenges before us are re-
flected by our commitment to work in a productive and cooperative
manner that will exploit our individual Department’s scientific
strengths and unify them into a productive, responsive and fully in-
tegrated research effort, the RWG’s Working Plan.

As I have alluded, the path of science is difficult; it is challeng-
ing, expensive and time consuming. Easy and complete solutions to
such complex health problems are very attractive, but are ex-
tremely rare. My written statement summarizes new directions
and accomplishments for the DOD. I feel that the challenges are
great. There are no quick solutions; however, we remain committed
to the responsible and aggressive pursuit and resolution of these
problems.

That concludes my statement, and I will be happy to answer any
questions that you might have.

Mr. Towns [presiding]. Thank you very much, Dr. Winegar.

[The prepared statement of Ms. Winegar follows:]


144

Dr. FEUSSNER. Yes, sir.

Mr. SHays. Let me just—one last point. I am sorry, but I want
to get on the record—the VA officials, and I should have gotten the
name of the individual in the report—Dr. Murphy, described, char-
acterized the registry as “a very crude health surveillance tool,”
and a primary source of primary hypotheses for subsequent re-
searcl

I want to know what role the registry plays, the Gulf War Health
Registry plays in our research?

Dr. FEUSSNER. Specifically regarding treatment?

Mr. Says. Just in terms of guiding any research.

Dr. FEUSSNER. Well, I think that it is—it collects information on
patients, it identifies symptoms; issues of fatigue, issues of
myalgias and muscle problems, issues relating to cognitive impair-
ment have been detected on the registry. I think that those prob-
lems are potential treatment targets. As I say, my impression is
that patients have been getting treatments that are symptom-
based, but there have not been systematic clinical research treat-
ment protocols that we have embarked on as yet.

Mr. Suays. I will just conclude by making a statement. I had Dr.
Rosker who told me he was not aware of the two studies I made
reference to in regards to the viability of the masks. He told me
that he would work hard to have them released and put on the
Internet, and it still hasn’t been done. And when people like your-
self don’t have access to those studies, I find it beyond my patience.

I am going to personally write the President of the United States
to ask him to intervene. I am going to ask you, Dr. Winegar, be-
cause you are aware of those studies, to make sure that we find
a way that people in the VA get to see these studies, and I am
going to pursue this. This is classified information that I can’t dis-
close publicly, other than to say it exists, which I am allowed to
do. And I am determined, after 5 or 6 years, that these reports be
made public, unless someone can tell me why there is a national
interest reason why it can’t be, and why someone like Dr. Feussner
can’t get access to that report. Reports, two. Excuse me, two.

You are on.

Mr. SANDERS. I will be very brief, because I look forward to hear-
ing the next panel.

No. 1, I look forward to working with you, Dr. Feussner. We can
maybe just chat for a few minutes and then decide how we will pro-
ceed.

My question, my brief question to Dr. Winegar, maybe you an-
swered that in terms of what Mr. Kucinich was asking, but I am
still not quite clear. I hope very much for a dozen different reasons
that there is not a war in the Gulf, but what is the position of the
DOD regarding pyridostigmine bromide and the administration of
that drug to the men and women who are over there right now?
Are you asking a waiver from FDA? What is going on with that?

Ms. WINEGAR. No. We have no plans at this time to use
pyridostigmine, nor have we made any request to the FDA for any
waivers,


12

© The use of pyridostigmine pretreatment, in conjunction
with atropine and pralidoxime treatment, improved
survival or animals exposed to soman. Limited human
evidence suggests that the proposed dose of
pyridostigmine will provide a level of enzyme
inhibition in humans comparable to that achieved in
animals which were protected from soman-induced
mortality.

© ‘There is extensive experience in humans with myasthenia
gravis ueing doses of pyridostigmine much greater than
those proposed in thie treatment protocol, and we have
no specific safety concerns with the proposed military
dos:

° We agree with DoD that withholding treatment from an
individual, based on personal preference not to receive
the pretreatment with pyridostigmine, could jeopardize
the health and safety of that individual or other
military personnel in the event of a chemical attack.

Although the implementation of the approved treatment protocol
for pyridostigmine was not problem free, no such implementation
difficulties meaningfully call into question any of these
determinations made by the ICWRG.

Similarly, the proposed treatment protocol for pentavalent
botulinum toxoid vaccine also was thoroughly reviewed by the FDA.
In adopting the staff recommendation, the Commissioner responded
to DoD:*

Based on your assessment of the military operation, I find
that there is no available satisfactory alternative therapy
for the prevention of botulism, and I concur with your
assessment that informed consent is not feasible and that
withholding treatment would be contrary to the best
interests of military personnel.

When the vaccine, which was in very limited supply, and the

% Letter to Assistant Secretary of Defense (Health Affairs)
from Commissioner of Food and Drugs, December 31, 1990.


172

Now any psychiatrist will tell you that you cannot make the di-
agnosis of PTSD with one of these scales, one of these instruments.
It takes a psychiatrist’s examination.

Well, in these studies they found that 10 to 15 to 20 percent of
veterans had a slightly elevated score on the PTSD scale. People
jumped at that, because it substantiated the policy, and they said
well, that confirms the policy. This must be stress. It must be mild
PTSD, and therein verified the policy. However, I recently pub-
lished an article in the American Journal of Epidemiology which
has been absolutely ignored, but which shows definitively that
those studies did not show that there is anything wrong with these
veterans having to do with stress, and that’s all the evidence that’s
used to back up the stress argument. In fact, this is the “Emperor’s
New Clothes.” Any doctor in the military who is worth their job
must believe this is stress, when, in fact, there is absolutely not
one shred of evidence that stress has anything to do with this prob-
lem.

All the time, however, VA psychiatrists were examining these
veterans, finding no PTSD, finding no stress-related illness, and
yet they couldn’t speak up. Why? Because that would have been to
speak out against the policy and I think they would not have been
in their jobs long.

Third: Now, instead of getting busy on an epidemic investigation
with a case definition, case control studies which probably would
have solved the problem, instead we undertook large statistical
studies with computers and comparing the 700,000 deployed with
the ones who were not deployed. You recall the results published
in the New England Journal of Medicine: No excess mortality, hos-
pitalization or birth defect rates in the deployed group compared
with those not deployed. The Iowa study was a similar study show-
ing very little difference in symptoms.

low, although this strategy seems scientifically sound and has
been widely touted, Published in the New England Journal of Medi-
cine, presumably refereed by some good people, it was actually a
terrible mistake. The problem was very subtle, but very malignant.
Let me explain.

By comparing the prevalence of individual symptoms or mortality
or whatever in the deployed versus the nondeployed groups, you
are unable to measure the impact of a Gulf war syndrome; if there
is a real disease or an injury, a brain injury or whatever, you can-
not see it in that kind of a study, and the reason is because the
real disease only affects about 10 to 20 percent of the deployed,
right? And therefore, its impact, its symptoms or mortality or
whatever are too small. They get washed out by being combined
with this large group, all of the rest of the deployed who are not
sick. So you don’t see a difference in these big studies. The dif-
ference, the disease can only really be seen by a case control study
in which you first find out who has the disease and compare them
to controls. Then you see big differences. We did that in our study
and we found big differences. However, our study was shunned be-
cause it went against the policy.

Now, in these studies another interesting thing happened. I had
also written an article, which will come out in next couple of
months in the American Journal of Epidemiology, which showed


44

() Although subjects may be familiar with procedures, never assume that he or she
ccomprehends everything.

£. Provide a written description of any reasonably foreseeable risks or discomforts to the
subject.

(1) For studies of potential subject benefit, describe risks unique to the study,
estimate their severity and likelihood, and/or compare these risks with the risks which
the subject may encounter in the course of daily activities and include any possible
risks to pregnant women, if applicable. If similar research has been conducted in the
past, describe the incidence of adverse effects or injuries which have occurred in
previous subjects,

(2) For studies of no potential benefit to the subject, list all risks which are more than
“minimal” (risks which are greater, considering probability and magnitude, than those
ordinarily encountered in daily life or during the performance of routine medical
tests).

(3) Where applicable, the subject will be advised:

(a) that a certain treatment of procedure to be used may involve risks that are
currently unforeseeable; and,

(®) of any precautions which are to be observed by the subject before and after
the study.

g. Provide a written description of any benefits to the subject or to others which may
reasonably be expected from the research (mention remuneration if any). It should be noted

that for studies in which a considerable sum will be paid, that payment should be prorated
and not paid in a lump sum, or a disproportionately large sum, at the completion of
Participation.

‘h. Provide a written disclosure of appropriate alternative procedures or courses of treatment,
if any, that might be advantageous to the subject, ¢.g., whether treatment is available outside
of the protocol/proposal.

i. Provide a statement to the subject describing the extent, if any, to which confidentiality of
records identifying the subject will be maintained. The possibility should also be noted that
representatives from the FDA, DOD, e.g. USAMRMC, may inspect the research records.
For studies utilizing military personnel, the following statement must be included: All data
and medical information obtained about you as an individual will be considered privileged
and held in confidence; you will not be identified in any presentation of the results. Complete
confidentiality cannot be promised, particularly to subjects who are military personnel,

35


85

7

on-one treatment of an injured or sick patient by a physician is
quite different from the administration of large-scale
prophylactic treatment.

Seventh, consideration must be given to the “nature of the
disease or condition for which the preventive or therapeutic
treatment is intended,* such as whether it is fatal. §

50.23 (d) (2) (iii).

Eighth, the Commissioner will consider the nature of the
information to be provided "concerning the potential benefits and
risks of taking or not taking the drug." § 50.23(d) (2) (iv).

Even if consent is not required, comparable information will be
provided.

Ninth, determinations that informed consent is not feasible
because of military combat exigencies are time-limited, and may
be revoked. § 50.23(d) (4).

Tenth, and most importantly, the "Commissioner may find that

informed consent is not feasible only when withholding treatment
would be contrary to the best interests of military personnel.”
§ 50.23(d) (1) (emphasis added) .

To repeal the regulation, as urged by the petitioners, would
be a declaration that informed consent is never infeasible under
military exigencies, including actual, effective use of weapons
of mass destruction, which will have fatal effects, for which no
alternative therapy is available, and in connection with which
withholding the IND would be clearly contrary to the best
interests of the troops.

5. The current rule is fully consistent with law and
ethics.

The legality of the interim final rule was challenged in
court by the same group that has now filed the current petition.
The courts ruled that the rule is fully consistent with law. The
District Court held:

The DoD's use of unapproved drugs does not involve the type
of scientific investigation under controlled circumstances
that “research” connotes. On the contrary, the DoD has


176

and research delving too directly into hypotheses of environmental causes were discouraged by
lack of funding. Here are some of the systemic effects:

1. Since no case definition of Gulf War syndrome was sanctioned and doctors were
forbidden to record it as a diagnosis, the CCEP and the VA registries found only
the other conditions that active duty troops might have in addition to their Gulf War
syndrome, but they “found” no Gulf War syndrome. ‘This led to the ubiquitous
expression, "There is no single disease, only a variety of symptoms,” as a self-
fulfilling prophecy-a reaffirmation of The Policy. When confronted by soldiers
with severe, disabling physical and cognitive symptoms, they recorded diagnoses
like “somatization disorder” and “adult attention deficit disorder." (Somatization
disorder (formerly hysterical neurosis) is exceedingly rare in men, rarely, if ever,
begins after puberty, and is characterized by changing symptoms. “Adult ADD* is
always preceded by childhood ADHD. These are not the problem, but they fit The
Policy.)

2. Sixteen surveys of returning veterans using the Mississippi PTSD Scale found
slightly elevated scores, and even though they were not high enough to qualify as
PTSD, they were widely quoted as proof that the veterans" symptoms were
Psychological problems caused by "stress." I recently published an article in The

(November 1, 1997) showing that the stress
argument was based entirely on a misinterpretation of the Mississippi PTSD scores.
Itis "The Emperor's New Clothes." Now, all that time, VA psychiatrists were
‘examining the Gulf War veterans and finding no PTSD or anything that could be
called a “stress-related illness." And yet, none of them spoke out against the stress
theory (The Policy). Since I published my paper in November, you don't hear
anyone mentioning the *S word" anymore, but millions of dollars more are about to
40 into stress research—more reaffirmation of The Policy.

3. Instead of getting busy on epidemic investigations with a case definition,
‘government epidemiologists undertook large computer analyses comparing the
veterans deployed to the Gulf War and those who were not deployed to the war.
‘You recall the results published in The New England Joumal of Medicine in late

JAMA in January 1997 was another example. Although this strategy scemed
scientifically sound and has been widely touted, it was in actuality a terrible
mistake. The problem is very subtle but malignant. By comparing the prevalence
of individual symptoms in the deployed and nondeployed populations, you are
unable to measure the impact of the Gulf War syndrome. This is because it affects
only 10 t0 20 percent of the deployed and its impact is washed out by the far larger
numbers of well veterans in the deployed group. ‘This problem can only be
overcome by employing a case definition derived directly from ill Gulf War
veterans, And yet, a case definition is against The Policy.

4, In these studies, the researchers inexplicably overlooked severe biases in the study
design that masked real and important increases in mortality, hospitalization and
birth defects. I recently authored a paper documenting the errors in those studies,
which has been accepted for publication in The American Journal of Epidemiology.

3


202

Dr. HALEY. Yes. It would be the worst thing I could imagine for
that to be taken as a dogma the way the opposite view, that there
is not one illness, has been taken as a dogma and has determined
the research.

Mr. Suays. Fair enough. And I don’t know if I am going to
change my ways, but at least you have me thinking.

Do you have any more questions? I am happy to wait. I am done.

Mr. SANDERS. Two more questions, Mr. Chairman.

Mr. SHays. I wanted to make a point. You have as much time
as you want.

Mr. SANDERS. Thank you.

Dr. Heivilin, it goes without saying, Dr. Haley is now working on
a treatment protocol and he will be finished in 6 or 8 months.
Those results will be published. Common sense would suggest that
if he has success, that we would immediately amplify that and we
would go on from that; is that correct?

Ms. HEIVILIN. We would want to replicate it, yes.

Mr. SANDERS. Try to replicate and hopefully we would have
something in it, et cetera.

Right now, do we have a list of those physicians who are doing
different treatments and seeing how well or how not well they are
succeeding?

Ms. HEIVILIN. No, we do not. And that is what one of our rec-
ommendations was leading to; we have a register of the first exams
that were given to the Gulf war veterans who signed up for the
register, but we don’t have anything on the followup. The followup
is being done individually by individual physicians. In some cases
there might be a case monitor, but that isn’t necessarily a physi:
cian, and that isn’t necessarily someone who is looking at what is
working and what isn’t.

Mr. SANDERS. I can think of at least three physicians now who
claim—who have done work with Gulf war veterans who claim to
have had some success, but I gather we have—there is no protocol
right now which says, OK, let’s double check, let’s—what is the ex-
pression you use—expand this or whatever we may do. Isn’t that
fairly absurd?

Ms. HEIVILIN. What we have heard from the VA is that this is
very expensive, very expensive to do, and they claim that their
data system, which has information on, all their patients on it,
would just be too expensive to extend to do this. re are other
ways, there are other cheaper ways to do this. We don’t necessarily
have to wait for automated data systems.

Mr. SANDERS. There are hundreds of treatment protocols out
there, aren’t there? How many—please help me, Dr. Heivilin. How
many folks out there are even saying we are treating——

Ms. HEIVILIN. I haven't the slightest idea.

Dr. HALEY. Oh, yes. Every doctor who is seeing these people in
a VA or private office is trying different treatments, experimenting,
and that is what ought to be done. It is just what is lacking is co-
ordination and recording, measuring the results to see if what the
doctors think is a result really is a result. Some objective measure-
ment.

Mr. SANDERS. But it is not really true that within the VA sys-
tem—for example, I mean Prozac is still being given, I mean you


62

and to relate this characterization to what is known about multiple chemical sensitivity (MCS)

and related conditions and disorders within ci

ian populations. The goal of the workshop is to
develop a research plan that builds upon existing efforts to understand MCS and related
conditions within the context of the known environmental exposures during the Gulf War. It is
expected that the plan will focus on individual factors that could affect susceptibility to low-level
chemical exposures, and on the development of acceptable case criteria for MCS that can be used
in future clinical and epidemiological research. The plan will also set forth a multi-year program
for the development of biomarkers that can be used to document chemical exposure.

Attendees to this conference will include those in the public and private sectors who are
most engaged in and affected by the multiple chemical exposure problem and whose personal
experience and/or profession expertise would add new information regarding the health effect of
multiple chemical exposures relevant to the Gulf War experience. These would include
scientists with recognized expertise in the area of MCS and related disciples of neurobiology,
immunology and endocrinology; prominent advocacy/treatment consumer group representatives
and other stakeholders; research scientists and policy makers from appropriate government
agencies, including State health departments, HHS, DoD, VA, and the Environmental Protection
Agency (EPA).

In addition, in FY’98, HHS will augment funding for an existing NIH Grant
Announcement, entitled “Chemical Mixtures in Environment Health” (RFA:ES-98-002, NIH
Guide, Volume 26, Number 38, November 21, 1997). This announcement is a joint effort of
NIEHS and EPA. The announcement seeks to fund research projects that will expand our

knowledge of the health effects of chemical mixture exposures, including an exploration of the


responded to very real circumstances and chosen what it
views as the best alternative given current knowledge. The
primary purpose of administering the drugs is military, not
scientific. The fact that the DoD will collect information
on the efficacy of the drugs does not transform the
strategic decision to use the unapproved drugs in combat
into research. Furthermore, the FDA has interpreted the
FDCA to permit using unapproved drugs in a *treatment-
investigational setting" in the past. . . . The FDA,
therefore, does not view every use of unapproved drugs as
research, and nothing in the DoD Act [10 U.S.C. 980,
requiring informed consent in DoD "research"] suggests that
Congress intended the term to have such a Lroad meaning.

Doe v. Sullivan, 756 F. Supp. 12, 15-16 (D.D.C. 1991).

The Court of Appeals for the District of Columbia affirmed
this decision in favor of the Government. The Court ruled:

While it is true that the FDA's prior interpretation of
the words "not feasible" [in section 505(i) of the Act]
focused on the subject's condition, the agency here has not
reversed course. It has simply added a tightly
circumscribed set of urgent circumstances in which the main
rule of informed consent, with fidelity to the statute's
terms, can be displaced. .

Doe v. Sullivan, 938 F.2d 1370, 1382 (D.C. Cir. 1991) (opinion by
Judge Ruth Bader Ginsburg) .

Not only was the regulation fully upheld by the courts, it
is also consistent with ethical standards. The primary issue in
the ethical analysis is: Does the use of INDs by the military in
the circumstances of the interim final rule constitute "research"
in the context of ethical standards which prohibit nonconsensual
xesearch on human subjects? The Belmont Report? discussed the

distinction between research and treatment:

? The Belmont Report, Ethical Principles and Guidelines for
the Protection of Human Subjects in Research, The National
Commission for the Protection of Human Subjects of Biomedical and
Behavioral Research, OPRR Reports, April 18, 1979.


121

Mr. SHays. We have lawsuits, we have workers who are getting
financial assistance from businesses because the businesses were
sued because of low-level exposure to chemicals; and they have
chronic illnesses, and some have died. I mean, that’s what is hap-
pening in the private sector, the world I know.

Ms. NEWTON. Clearly there are low levels of some chemicals that
can cause illness and death.

Mr. SHAys. The comment I heard from you is that there are some
chemicals for which low-level exposure can cause illness and death.
I mean, I think that’s pretty basic. So then the question is that
some chemicals may and some chemicals may not.

Dr. Feussner, your comment to me basically is that, in essence,
you can’t disprove that it doesn’t; therefore, you make the assump-
tion that it may until you know otherwise. Correct?

Dr. FeussNER. Yes, I think it is possible, yes.

Mr. SHays. Therefore, because it is possible, you don’t use it to
prove that it can’t happen because you don’t know. You make an
assumption that it may and, therefore, respond accordingly. And
that was one of the problems we had with the VA and the DOD.

For about 3 years they didn’t even want to look at any potential
chemical exposure, we didn’t fund any chemical research; and it
was not until the DOD basically had to acknowledge on a Friday
night at 4 that maybe, perhaps some of our troops might have been
exposed to chemicals at Khamisiyah. And we have already made an
assumption that every place that we bombed that was a chemical
plant or a biological piant, that the plumes went away from us, not
toward the troops, which was another gigantic assumption.

So what you have said to me—basically, what the panelists have
said to me, is that the answer is, “no, but.” You have qualified your
answer by saying, “some may.” And I tell you that I am not a
Ph.D., I am not a doctor, as you know, and I think it is insane that
we have one standard in the private sector and a whole different
standard in the public sector with the military.

That’s one of the reasons why—your answer to that question is
one of the reasons why some of us want to give this to somewhere
else. Because I could have a number of doctors in the private sector
who would say, uf course, Congressman, that is the case, and then
it just depends on what chemicals and it depends on what level.
That would have been the answer I would have gotten from people
in the private sector, not people from the public sector.

Your answer to that question is one of the reasons why we want
someone else to do the research.

I would like to tell you another thing that distressed us. The
other thing that distressed us was that when we asked the VA how
many doctors they had who had any background in chemical expo-
sure, they could only name one out of the thousands and thou-
sands; and then when we said, please submit it in writing, they
could give us a handful. And I gather that the schools don’t teach
it and we don’t have it; and I want to know, on this panel, who
has expertise in chemical exposure?

Dr. FEUSSNER. I do not.

Mr. GERRITY. For 10 years I conducted clinical research for the
Environmental Protection Agency at their Health Effects Research
Laboratory, Clinical Studies Division, in Chapel Hill, NC. Before I


195

be eminently sensible. Maybe you will fail and maybe we will learn
something that doesn’t work.

Dr. HALEY. Five 's that don’t work; that’s great.

Mr. SANDERS. What I cannot understand from the very beginning
is why we have not done this in 100 instances.

Dr. CLauw. I would just like to say again, I think you need to
be real careful about blaming the people who were sitting on this
front panel. If the exact same treatment trial for chronic fatigue
syndrome or for fibromyalgia were proposed; it likely would get
panned. It has been, it will get. So be careful about saying this is
a problem specific to the Gulf war. The problem is that these ill-
nesses are so nebulous, so hard to define and so little about them
is known that they don’t do well in the peer review process. So
again, this is not something that-——

Mr. SANDERS. I am very upset at what has happened in the last
7 years. I don’t agree with that assertion. I understand that it is

ifficult, but we have not done a good job.

Dr. CLauw. I don’t disagree with that either. You’re right.

Dr. HALEY. The system doesn’t want this done. That’s the prob-
lem. The peer review groups would not go for any of this research.

Mr. SANDERS. Are we all in agreement, though, this seems pretty
“common sensible”? I am delighted to hear that Dr. Haley is doin;
work, you will publish your results, they will be partially Zuccessful
or fail, and we will learn from them. Is there any disagreement
that we should be doing this all over the place?

Ms. HEIVILIN. One of the recommendations that we have made,
that we have discussed quite extensively, is that we think that
both the VA and the DOD should be following the treatment of the
veterans, because they are all being treated for the symptoms that
they have, and we should find out what is working that certain
doctors are using, and share that information, because there might
be some possible treatments out there that are working quite well
that no one knows about, or very few people know about.

Mr. SANDERS. My last question, Mr. Chairman.

I believe, based on what little I may know in the concept of mul-
tiple chemical sensitivity, and I think we should be able to learn
something, that if somebody walks into a room for Gulf war vet-
eran or nonGulf war veteran, walks into a room where there is per-
fume or different types of chemicals, and that person reacts, we
should be learning something from that process, I should think.
That should teach us something.

Now, what has concerned me all along, and I would like some-
body to comment on this, as to whether or not we have 70,000 or
100,000 time bombs out there, are we being fair to the veterans by
saying to them, stay away from perhaps this type of food or chemi-
cals in our food? Stay away from this type of pollution to the degree
that you can.

Stay away from, you know—maybe people are getting ill and
they haven’t even seen the cause and the effect. Do you follow what
I am saying? Is what I am saying making any sense?

Mr. CHAN. That’s one solution, yes. And I think that hopefully
with those people we can find out what could possibly be a cause,
what is common. Were they located in the same area, were they
doing something, were they getting vaccines? I mean instead of


124

yes, this particular chemical is the source of all of these particular
incidents.

The difficulty—but having said that, there is a lot of anecdotal
stuff out there. There has been testimony before these—before this
committee that all of us, when we go home, hear some of the anti-
dotes. So what I worry about is the methodology by which research
is either conducted or approved.

By that I mean this: If you—it seems to me appro riate that you
do at least some studies which measure the Gulf—those who were
deployed to the Gulf and those who were not. Those are big, com-

licated studies, and they will show you perhaps—you know, they
fave to be done because you need to know is there a different
death rate, is there a different illness rate? But I suspect that to
really get quality research, to try to draw the connection between
the scientific research and the antidotes, to figure out whether or
not there is something there, you have got to look either at the
folks sitting around in Burlington, VT—all of them say, yes, I have
got the same kind of sensitivity to candles—or you have got to go
back to the Gulf and try to figure out who was in a particular place
at a particular time.

Now, I understand how difficult that is. But it seems to me that
the attitude with which you look at the proposals that are coming
is really important, very important, in trying to figure out what
kinds of proposals will be funded. And it seems to me that it is
critically important to look for those proposals which are trying to
find a connection, trying to find a chemical or a certain mix of
chemicals with a smaller group, so you are not just doing the global
studies, those deployed and those not deployed.

And I guess what I would like is a reaction to that comment, and
whether, when you are looking at proposals trying to figure out
which ones to approve and which ones not to approve, how you are
taking into consideration those—how you are taking those kinds of
issues into consideration.

Dr. FEUSSNER. Well, I think that the external peer review groups
are receptive to novel hypotheses that can be tested rigorously so
that the hypothesis, as posed, can be answered. And basically
that’s the essence of the scientific method, that there is a hypoth-
esis or a question that you are asking and that the measurements
you are proposing to make will answer that question either in a de-
finitive way or in an innovative way.

The difficulty in my mind with low-level exposures is that as the
exposures are large and cause serious, acute problems, we are able
to associate the exposure with the outcome. As the exposure be-
comes more subtle and the outcome less precise—for example, your
blood pressure falls, which is something you can measure precisely,
versus you have subtle cognitive memory defects which are harder
to measure, no less pertinent, certainly, but harder to measure de-
finitively, I think the research problem becomes more difficult.

My impression is that the review committees are open to vir-
tually any testable hypothesis, and I have seen no evidence that
that is not the case.

Mr. . Well, my—I guess my concern is, is there—are there
any guiding policies or anything to guide these—the independent—
the peer review organizations to—I mean to say we are simply


31

‘consent approvals are obtained from The Surgeon General HSRRB. Proposal requirements for
studies involving human subjects are at Attachment 3. Similarly, use of animals in research is
prohibited until protocols have been reviewed and approved and the regulatory requirements of
the 1966 Animal Welfare Act (P.L. 89-544) as amended in 1976 (P.L. 94-279) and 1985 (P.L.
99-198) and as implemented through DoD Directive 3216.1, The Use of Animals in DoD
Programs, 1998. Proposal requirements for studies involving animal subjects of research are
shown at Attachment 4.

In addition to full and open competition, noncompetitive awards may be made to support
program administration and management, fulfill sole source requirements for unique capabilities
including those directed by the Congress, and to conduct intramuural-Federal laboratory-research,
Examples include awards under existing contract vehicles for studies and management assistance;
contracting with the National Academy of Sciences for assistance to DoD in the conduct of
epidemiological study of veterans who were in the vicinity of the Khamisiyah demolition; as well
as studies in DoD facilities that have specialized containment facilities, equipment and standard
‘operating procedures for work with chemical or biological warfare agents,

‘GWVI Investment and Accomplishments

The DoD's RDT&E funding for GWVI research from FY94 through FY97 totals $62.6M.
From FY98 through FY02, the Department estimates investing approximately $20M per year in
GWVI specific research and thereby bringing the total since FY94 to approximately $160.8M.
This funding profile does not include related funds for health care delivery or our investments in
highly relevant, core science and technology efforts (e.g., the medical chemical defense program)
which are already established, continuing programs that will likely have direct benefits for the
GWVI research program.

Reporting total Defense Department funding for the GWVI program (i.e, including related
projects) is complicated and somewhat subjective since there is no bright line demarcation
between GWVI-specific funded projects and those related projects embedded in the DoD core
science and technology programs. As I will mention later, the DoD has established a separate
Program 6 RDT&E program element and project for GWVI specific research beginning in FY99,
Establishment of this program will facilitate Departmental (e.g., ASBREM, Technology Area
Review and Assessment (TARA) and Defense Science and Technology Advisory Group
<DSTAG)) and Congressional reviews of resource expenditures, programs and budgets, as well as
program accomplishments and plans.

The investment in GWVI is providing new information on the impact of military service in the
Gulf War on health-related problems, providing new areas of research exploration, and prompting
new force protection initiatives that provide for medical surveillance during future operations.
With specific reference to GWVI, the investment and findings have highlighted the need for
improved prevention, intervention, and treatment approaches, and the natignal program has
responded to these needs both in its approaches for veterans’ health care and in the RWG
emphasis on its research investment strategy.


156

years after the war ended, questionnaires were being distributed
requesting information from veterans on their exposures to certain

agents during the war.

INITIAL GOVERNMENT RESEARCH EMPHASTZED STRESS; OTHER HYPOTHESES
WERE NOT PURSUED UNTIL LATER

Early federal research appeared to emphasize risks associated with
psychological factors such as stress. To support this emphasis,
DOD pointed out that the psychological state of mind can influence
physical well-being. DOD also pointed to a recent argument that
from the American Civil War onward (and perhaps even earlier), a
small number of veterans have reacted to the stress of war by
suffering symptoms similar to those reported by some Gulf War

veterans.*

Of the 19 studies initiated before 1994, roughly half focused on
exposures to stress or the potential for posttraumatic stress
Gisorder (PTSD) among returning troops.’ As late as December 1996,

the Presidential Advisory Committee noted that “stress is the risk

*K.C. Hyams et al., "War Syndromes and Their Evaluation: From
Civil War to the Persian Gulf War,”
vol. 125 (1996), pp. 398-405.

’an additional 3 of the 19 studies did not provide information
about veterans’ illnesses but were instead building databases or
methods to be used in later studies. Notably, according to PGVCB,
none of these 3 studies had been completed as of June 1997.

8


179

Mr. SHays. One of the things, Doctor, we tried to do early on is
to say, “let’s put the blame everywhere to see if we could have that
bureaucratic hold kind of loosened.” In other words, we will start
fresh and not cast aspersions anywhere. But we still see it is very
difficult to let go.

Dr. HALEY. There is a very strong belief that this isn’t real. We
are not going to do studies that could show it.

Mr. Suays. I hear you.

Dr. Clauw. Dr. Clauw, you came before us as well, is that cor-
rect?

Mr. Cuauw. Yes, I did.

Mr. SHays. What was the hearing that you came before us? Do
you remember the hearing, how long ago it was?

Mr. CLauw. About a year ago.

Mr. Suays. March of last year?

Mr. CLauw. Yes.

Mr. Suays. Thank you.

Dr. CLauw. Mr. Chairman, members of the subcommittee, I ap-
preciate the opportunity to give my opinions on adequ: of the

vernment efforts to research causes and treatments of Gulf war
related illnesses. I would first like to briefly state my views on the
unique problems faced in researching these illnesses and then com-
ment on the strengths and weaknesses in the Government research
programs. I will conclude by making a few suggestions for how
these efforts might be improved.

As you all know, most of the research on Gulf war illnesses has
focused on the “unexplained” symptoms and conditions that have
afflicted tens of thousands of veterans who were deployed to the
Persian Gulf. These illnesses are unexplained because we are not
certain in many cases of the precise physiologic cause for the symp-
toms such as fatigue, memory problems and/or pain in various
areas of the body. In medicine when we don’t know the cause of
symptoms, then we likewise struggle with appropriate and effective
treatments.

Although much remains unknown about these symptoms and
conditions, I think that there are several irrefutable facts that have
emerged. The first is that there is not one unique or discrete illness
that occurred in veterans deployed to the Gulf war. Instead, these
individuals suffer from the same patterns of symptoms that afflict
millions of Americans and go by numerous over! lapping semantic
terms such as fibromyalgia, chronic fatigue syndrome, multiple
chemical sensitivity, et cetera. Also, some individuals with these
symptom complexes are inappropriately labeled as having a psy-
chiatric or psychological problem.

I would encourage anyone who is truly interested in Gulf war ill-
nesses to go to a meeting of patients that have fibromyalgia, chron-
ic fatigue syndrome, or multiple chemical sensitivity. It is easy to
find such meetings because these illnesses are so common in the
general population that such support groups exist in nearly every
city in the United States.

t you will find if you do this is that there is a room full of
people who will have the same exact symptoms that Mr. Sanders
described earlier, but who were never in the military or who never
have been anywhere near the Persian Gulf. You will also find prob-


Statement of
John R. Feussner, M.D.

Chief Research and Development Officer
Veterans Health Administration
Department of Veterans Affairs

Before the Subcommittee on Human Resources of thé
House Committee on Government Reform and Oversight
Research on Gulf War Veterans’ Illnesses

February 24, 1998
Kes

Mr. Chairman and members of the Subcommittee, thank you for this opportunity
to discuss the status of the current and projected federal research program on Gulf War
veterans’ illnesses. I serve as the Department of Veterans Affairs’ (VA) Chief Research
and Development Officer and the Chairperson of the Research Working Group (RWG) of
the Persian Gulf Veterans Coordinating Board. Today I will focus my presentation on the
strategy and objectives of the RWG.

First, I would like to provide some history of the RWG. The federal research
effort on Gulf War veterans’ illnesses involves scientists in federal, academic, and private
institutions, in the United States and abroad, whose research is sponsored by VA, the
Department of Defense (DoD), and the Department of Health and Human Services (HHS).
Each department has distinct, though complementary, capabilities for conducting and
sponsoring research on Gulf War veterans’ health issues, In addition, each department has
its own appropriations for extramural and intramural general biomedical research.

The primary charge to the RWG is to assess the state and direction of research;
identify gaps in factual knowledge and conceptual understanding; identify testable


206

Ms. HEIvVILIN. I would add, I think that we should spend some
time and money monitoring and documenting the health—the pro-
gression of the disease, the health of the veterans.

Mr. CHAN. I like to look at this whole thing very differently. I
think if you can imagine any contingency in the future where our
soldiers are going and that we have to sort of anticipate what
might happen to those soldiers and to look at it that way, you
know, find that a single person will not only be exposed to the po-
tential threat that is there, but also the environmental side that
is there, from malaria to infectious disease, and also what we im-
pose on the body of the soldiers, maybe a dozen or more different
vaccines in his body or her body, to put that under stressful condi-
tions, not knowing what the future is going to be like, and only to
realize that afterwards; the government may not even know where
he or she was, did not track, did not know where they were taken,
cannot accept the responsibility of taking care of them, did not
track their medical records and so on. I think it is doable if we do
it up front, because a lot of research and all of this kind of discus-
sion I have heard from PB to anthrax vaccine is that that a single
agent is safe, but no one ever tells me whether the measles or the
plague, the vaccine A, the B, and the mumps and rabies and all
of those things that they are given, you know—I mean I could see
antibody running through their body all the time, and yet we don’t
know if that is OK.

So I think I would address it from that perspective, other than
what new research needs to be done. I think we have to look at
it. We know these things. We know ahead of time how the sand
flies may cause harm to people and all these things that we give
shots to those soldiers for, and I think it is time to do it right now,
rather than wait until another potential Bosnia or someplace else.

Mr. SHays. You make a good point, Mr. Chan, and it is very well
taken and I think others would agree.

We will conclude this hearing, but I first off want to thank Dr.
Feussner for staying and listening to the second panel. That is
very—I think it is important that you did it and I thank you. Dr.
Gerrity, you are here as weil. And also Dr. Winegar, I appreciate
you being here. That is very nice and helpful. I would welcome—
I would just thank our panel, probably put in a pitch I think about
our working group, HHS, DOD and VA and one person from VA,
it would be nice to get a few veterans in there, maybe a veteran
who could just provide a reality to all of the researchers. Not a doc-
tor; just somebody who would say, “yes, but.”

I would ask any of our previous panel if they would like to just
come to put something on the record, I would be happy to have you
do that, just to make a statement. Do you, Dr. Feussner, just want
to make a comment for the record? Dr. Winegar? I just want you
to know you were invited to do that.

So thank you again. This hearing is adjourned. It was a very in-
teresting hearing, and I appreciate ali our participants and thank
our reporters.

[Whereupon, at 2 p.m.. the subcommittee was adjourned.]

e)


139

That is why I have concerns about the whole way we approach
this, because there is still this reluctance on the part of all of ye
to just accept the fact that our troops may have been exposed to
chemicals and we need to go overtime to deal with this. And it is
still there. It still came out in that first question. You wanted to
accept the most narrow way to respond to the question.

How do we determine chemical exposure? You answered yes, we
can detect chemical exposure. How do we detect chemical exposure?

Ms. WINEGAR. We have a number of different methods for detect-
ing the known chemical warfare agents. Again, I am sorry if my
answer is limiting to you, but that is the priority and the mission
of the DOD. It is not within our purview or our mission to measure
for every possible chemical that occurs in the environment. We
don’t have the capability to do that.

Mr. SHAys. Well, one of the reasons we didn’t detect is we didn’t
think there was offensive or defensive use of chemicals. We made
an assumption that our chemical fumes were going in one direc-
tion. Is it your testimony that the known chemical agents that we
have don’t lead to chronic illness and death?

Ms. WINEGAR. I don’t think that we have any data one way or
the other on very low levels of exposure to those chemical warfare
agents.

Mr. SHays. When did you learn that our troops were exposed to
low level chemicals? When did you learn it?

Ms. WINEGAR. I learned it at the same time everyone else did:
when the announcement was made.

Mr. SHAys. Were you outraged that you didn’t know sooner?

Ms. WinEGak. It is not within my jurisdiction. As I indicated ear-
lier, my responsibility is in the research—

Mr. Suays. I am just asking you as an American who was—were
you working at DOD at that time?

Ms. WINEGAR. Yes.

Mr. Suays. Were you outraged?

Ms. Winecakr. I was surpri

Mr. SHays. Not outraged?

Ms. WINEGAR. No, I don’t think so.

Mr. SHays. You weren’t outraged that CIA had this information
and DOD had this information for years and didn’t come forward
until we were going to have a hearing to expose it? That didn’t out-
rage you?

Ms. WINEGAR. No, I don’t think so.

Mr. SHays. Why not?

Ms. Winecar. It takes an awful lot to outrage me.

Mr. SHAys. See, that’s the other reason why I think we need to
move it away from this panel, because I want people, and I think
others do, who get outra; a little sooner. They are not outraged
when soldiers come to them that are sick and describe their ill-
nesses and say an alarm went off.

See, I asked you about detection because I want to know how we
detect it on the body. But we had detections. We had equipment
that a lot of soldiers were given. They didn’t go on before the war,
they went on during the war. Then we were told the hundreds of
alarms that went o! during the war were all false, because they
weren't calibrated right, and then we had testimony from two sepa-


147

sponded to legislative requirements. For example, the three studies

on low-level chemical exposure which were funded by the coordi-

nating board were funded in direct response to congressional man-
late.

By the time the research was accelerated and broadened, oppor-
tunities had been missed to collect critical data that cannot be ac-
curately reconstructed.

Second, the Government’s early research emphasized stress as a
cause and gave other hypotheses such as multiple chemical sen-
sitivity short shrift. Although veterans raised concerns about po-
tential chemical exposure soon after the war, the Federal research
plan was not modified to include these concerns until 1996, when
DOD acknowledged that potential exposures to chemical agents at
Khamisiyah Iraq.

Third, in contrast, the private sector pursued research on low-
level exposures to certain chemical warfare agents or industrial
chemical compounds. Although the government argued that there
was no evidence that low-level exposure can have adverse health
effects, we found a substantial body of research which suggests oth-
erwise.

For example, abundant evidence from animal experiments, stud-
ies of accidental human exposures, and epidemiological studies of
humans shows that low-level exposures to certain organo-
phosphorous compounds, including sarin nerve agents to which our
troops were exposed, can caused delayed chronic neurotoxic effects.
In addition, research that we reviewed also indicates that agents
like pyridostigmine bromide, also called PB, which the Gulf war
veterans took to protect themselves against the immediate life-
threatening effects of nerve agents, may alter the metabolism of
organophosphates in ways that activate their delayed chronic ef-
fects on the brain.

Fourth, the Government funded little research on treatment.

Finally, while the Federal Government research strategy heavily
emphasized epidemiological research, we believe that the ongoing
epidemiological research cannot provide precise, accurate, and con-
clusive answers regarding the causes of the veterans’ illnesses be-
cause of methodological problems. To date, most of the studies com-
pleted are epidemiologic studies and at this point there has been
no light shed on causes or possible treatments.

There are a number of reasons for this. First, researchers have
found it extremely difficult to gather information about many key
exposures. For example, medical records on the use of PB tablets
and vaccinations to protect against chemical-biological warfare ex-
posures are inadequate. Second, Gulf war veterans were typically
exposed to a wide array of agents, making it difficult to isolate and
characterize the effects of individual agents or to study their com-
bined effects. Third, most of the epidemiological studies on Gulf
war veterans’ illnesses have relied only on self reports for measur-
ing most of the agents to which veterans might have been exposed.
Fourth, the information gathered from Gulf war veterans years
after the war may be inaccurate or biased. There is often no
straightforward way to test the validity of self-reported exposure
information, making it impossible to separate bias and recalled in-


158

accurate, dose-specific exposure information is particularly
critical when low-level or intermittent exposure to drugs,
chemicals, or air pollutants is possible. It is important not only
to assess the presence or absence of exposure but also to
characterize the intensity and duration of exposure. To the extent
that the actual exposure of individuals is misclassified, it is
difficult to detect any effects of the exposure. Another means of
inking environmental factors to disease is to determine whether or
not evidence shows that as the exposure increases, the risk of
disease also increases. However, this dose-response pattern can be
detected only if the degree of exposure among different groups can

be determined.

Finally, in addition to specific case definition and dose-specific
exposure information with known accuracy, it is important that a
sufficient number of persons be studied to have a reasonable
likelihood of detecting any relationship between exposures and
disease. To the extent that this relationship is subtle or
obscured in particular investigations by “loose” case definition
(that is, a case definition that is too broad and encompasses
different types of illnesses) or problems in measuring exposure,
larger samples would be required. For example, the Institute of
Medicine noted that "very large groups must be studied in order to
identify the small risks associated with low levels of exposure,
whereas a relatively small study may be able to detect the effect

of heavy or sustained exposure to a toxic substance. In this way,


46

the results of the pregnancy test which you were administered as part of the screening for this
study, you should not participate if you think there is a possibility that you might be
pregnant." Also, a statement should be included which directs the volunteer to notify the
principal investigator if she becomes pregnant while enrolled in the study. If women will be
withdrawn from the study should they become pregnant, that should be clearly indicated

p. For all USAMRMC-sponsored studies, the following statement must be included in the
consent form: It is the policy of the U.S. Army Medical Research and Materiel Command.
(USAMRMC) that data sheets are to be completed on all volunteers participating in research
for entry into the USAMRMC's Volunteer Registry Data Base. The information to be
entered into this confidential data base includes your name, address, social security number,
study name and dates. The intent of the data base is two fold: first, to readily answer
questions concerning an individual's participation in research sponsored by the USAMRMC;
and second, to ensure that the USAMRMC can exercise its obligation to ensure research
volunteers are adequately warned (duty to warn) of risks and to provide new information as
it becomes available. The information will be stored at USAMRMC for a minimum of 75
years.

4g. Provide a space for subject's typed/printed name and permanent address as well as space
for date and signature of witness and typed/printed name of witness.

5. In accordance with 21 CFR 56.111(a)(3), IRBs are responsible for reviewing the methods
used by investigators to recruit subjects. One method of recruiting subjects is through
advertisements which should be seen as an extension of the informed consent (see 21 CFR 50.20,
21 CFR 50.25). IRB review of advertisements is necessary to ensure that the information is not
misleading to subjects. The FDA recently established guidelines on advertisement for research
subjects. Generally, the FDA believes that any advertisement to recruit subjects should be limited
to:

a, The name and address of the principal investigator.

b. The purpose of the research and, in summary form, the eligibility criteria that will be used
to admit subjects into the study.

¢. A straightforward and truthful description of the benefits (e.g., payments or free
treatment) to the subject from participation in the study.

d. The location of the research and the person to contact for further information.

Provision of the advertisement used by the investigator to recruit research subjects must be
included with the protocol/ proposal submission.

6. The USAMRMC Human Use Review and Regulatory Affairs Division should be contacted
should a principal investigator have questions concerning these provisions or if the principal

37


6

quest for intramural proposals valued at approximately $5 million
for research on the neurobiology of stress, the neuroendocrine
sequelae of stress, and immunologic consequences of stress.

In June 1997, VA funded a multicenter study examining the ef-
fectiveness of a computerized battery of neuropsychological testing
that could improve the accuracy of the diagnosis of PTSD by ena-
bling the clinician to rule out organic central nervous system dys-
function.

In July 1996, VA funded a new multicenter treatment trial inves-
ligating the efficacy of trauma-based group therapy in the treat-
ment of post-traumatic stress disorder.

Finally, VA has issued a program announcement in August 1997,
requesting proposals for additional multicenter trials of PTSD
treatment. atment methodologies sought include novel, non-
pharmacological approaches to treatment, with special emphasis on
targeted subpopulations such as women and Gulf war veterans.

‘rom 1994 to present, the Research Working Group has worked
to coordinate and direct a diverse research portfolio consisting of
121 projects and a total cumulative investment of approximately
$115 million. Of these 121 projects, 39 have been completed, 78 are
ongoing, and 4 have been newly awarded and are awaiting startup.
There are 14 identified research focus areas ranging from the ef-
fects of service in the Gulf war on the brain and nervous system
to potential health consequences of low-level exposure to chemical
warfare agents. Approximately one-third of the projects are epide-
miological, one-third clinical, and one-third represent basic labora-
tory-based research.

the research programs of the Federal Government continue to
provide more results, we will increase our understanding of Gulf
war veterans’ illnesses, which will, in turn, enhance our potential
ability to diagnose and treat them.

Mr. Chairman, I will conclude my testimony here and answer
questions later.

(The prepared statement of Dr. Feussner follows:]


40

ATTACHMENT 3
RESEARCH INVOLVING HUMAN SUBJECTS/ANATOMICAL SUBSTANCES?

1. The USAMRMC policies and procedures governing the use of human subjects parallel those
of the Department of Health and Human Services (DHHS) as contained in the Code of Federal
Regulations, Title 32 Part 219 (32 CFR 219) and Title 45 Part 46 (45 CFR 46) Subparts B, C and
D. Assurance of compliance with USAMRMC policy must be documented by submission of a
completed Optional Form 310 (Protection of Human Subjects Verification Identification’
Certification/Declaration). This form is attached. This form must be completed by the
Chairperson of the Institutional Review Board. If the study is exempt, it should be noted in the
‘appropriate exemption blocks. The level of risk that has been assigned to the protocol (exempt,
minimal, greater than minimal) must be indicated in the comments block. This form is required
for all studies funded by USAMRMC (to include those studies only using anatomical substances).
Tf such documentation is not available, a statement from an approved institutional official
indicating full compliance with 32 CFR 219 and 45 CFR 46 may be used, after review by the
USAMRMC, to negotiate a special assurance regarding the use of human subjects in the research
project

2. Informed Consent Statements for the proposed research shall include those details described in
32 CFR 219 and 45 CFR 46, and in addition the special DA provisions listed in paragraph 3
below. The protocol, consent form and the advertisement used to recruit subjects, if applicable,
should be provided with the proposal. Paragraph 4 below contains the suggested elements of
informed consent which should be followed when constructing the consent form. Paragraph 5
contains guidance for constructing the advertisement notice,

3. Special Human Use Provisions in DOD Funded Research
a. Title 10, U.S.C., Section 980, Requirement for Obtaining Informed Consent states that

funds appropriated to the DOD may not be used for research involving a human being as an
experimental subject unless:

(1) The informed consent of the subject is obtained in advance; or

(2) In the case of research intended to be beneficial to the subject, the informed consent
Of the subject or a legal representative of the subject is obtained in advance.

In essence, if an individual cannot give specific consent, the person cannot be entered into a
study unless the prospective subject will receive some definitive benefit as a result of
participation. This is legally binding and there will be no exceptions.

> From U.S. Army Medical Research and Materic! Command Broad Agency Announcement 95-1

Bel


120

I am going to tell you some of the distressing elements of the
hearings and ask you to comment. Dr. Joseph, when he was work-
ing in DOD, said that basically low-level chemical exposure does
not lead to chronic illness and ultimate death. I want to know, Dr.
Winegar, do you believe that’s true?

Ms. Winecar. I think——

Mr. SHays. Not that he said it, but do you believe that low-level
chemical exposure does not lead to chronic illness and ultimate

leath?

Ms. Winecar. I don’t think that we have enough information at
the time for me to make a definitive statement like that. But just
for the record, I do want to clarify that I am not a physician and
feel unqualified to comment on patient care issues.

Mr. SHays. OK. What is your Ph.D. in?

Ms. WINEGAR. Microbiology.

Mr. Suays. OK. Dr. Gerrity?

Dr. FEUSSNER. He is also not a physician.

Mr. SHays. I am still going to ask everyone this question, and
if they want to discount their answer and if we have the wrong wit-
nesses, I apologize that we invited them.

Mr. GerRITY. My original training was as a physicist. I did post
doctoral training as a pulmonary physiologist.

Mr. SHays. Do you believe that low-level chemical exposure does
not lead to chronic illness and ultimate death?

Mr. GERRITY. I think that there is not enough information in the
scientific literature to—

Mr. Suays. Dr. Feussner?

Dr. FEuSSNER. I think it is possible that low-level chemical expo-
sure could lead to chronic illness. I think, unfortunately, there is
pot enough information to say definitively whether it is probable or

Me. Suays. Dr. Barrett?

Mr. Barrett. I would agree with Dr. Feussner’s statement.

Mr. Suays. Dr. Newton?

Ms. NEwrTon. I am sorry. Could you repeat the statement?

Mr. Says. Do you believe that low-level chemical exposure does
not lead to chronic illness and ultimate death?

Ms. NEWTON. I believe that that is—that there is insufficient in-
formation to answer that question.

Mr. Suays. The answer was insufficient information.

Well, tell me why I spent all of my time as a State legislator
making sure that OSHA established rules and regulations to make
sure that our workers were not exposed to low-level chemical expo-
sure because they would ultimately get illness and die?

Why does the military look at this issue so differently than we
do in the private sector? Why is there such a double standard on
this issue? I would love an answer. Did I waste my time for 13
years in the State house trying to protect workers from low-level
exposure to chemicals because we believed that it led to chronic ill-
ness and death?

Dr. FEUSSNER. I think—no. I think what you did is you tried—
in the absence of evidence about low-level exposures, you assumed
that there was danger until proven otherwise and so that you tried
to protect workers against low-level chemical exposures.


19

© A study of military hospitalizations has shown that, at least among active duty
personnel, the rate of hospitalizations of Gulf War veterans did not exceed that
of their non-deployed counterparts. This suggests that Gulf War veterans are
not experiencing more illnesses of a severity that would lead to hospitalization.
To account for potential bias from restricting this study to military hospitals,
the investigators are extending their study to include civilian health care
facilities.

* A substudy of the hospitalization study shows that infants of Gulf War veterans
have not been experiencing a greater prevalence of birth defects compared to
the infants of non-deployed era veterans. A more focused examination of the
tare birth defect known as Goldenhar Syndrome also failed to find any
statistically significant difference in prevalence in infants of Gulf War veterans
compared to non-deployed era veterans. Further studies of birth outcomes
continue to explore this concen.

‘© Recent research studies have provided important information on the
interactions of neurotoxins and other exposures. A recent study indicates that
stress can increase the penetration of PB across the blood-brain barrier
suggesting the possibility that PB could cause a central nervous system effect.
Another recently published study suggests that PB may decrease the levels of
permethrin in the central nervous system, thus potentially mitigating against an
adverse synergistic interaction between these two compounds. The federal
government has increased its research investment in research on the toxicology

of interactions.


4

Although issues around the potential health impacts on our troops of potential low-
level exposures to nerve agents are very important to us, there are other exposures and
health outcomes of concem as well. For example, the importance of musculoskeletal
conditions among Gulf War veterans is clearly evident based on the prevalence of these
conditions among veterans reporting to the VA and DoD registries, and on results
‘emerging from a number of research efforts including the Iowa study of Gulf War
veterans. The federal research portfolio contains significant research efforts to better
clarify the pathophysiology and clinical significance of musculoskeletal conditions in Gulf
War veterans. Of particular note are the efforts at the Portland VA Environmental
Hazards Research Center investigating the pathophysiology of Fibromyalgia (FM) and the
hypothesis that FM is a disease process that accounts for a significant amount of the
musculoskeletal symptoms in ill Gulf War veterans. Also of note, the DoD BAA from
1995 provided funds for three new research programs that employ multi-disciplinary
approaches to musculoskeletal function in the context of both pain and fatigue.

Because of the obvious importance of ensuring appropriate and effective treatment
of Gulf War veterans’ illnesses, the Department of Veterans Affairs, Office of Research
and Development formed a Planning Group charged with developing a Program
Announcement (a type of request for applications) inviting proposals within the VA
system, or in collaboration with DoD, for multi-center trials for candidate treatments of
clearly defined medical syndromes or illnesses among subgroups of Gulf War veterans.
‘The Program Announcement was issued in January 1998. In addition, VA and DoD are
proceeding with the planning of a joint VA/DoD multi-center treatment trial for Chronic

Fatigue Syndrome and Fibromyalgia in Gulf War veterans.


3

In previous hearings we have heard critiques and defenses of the
research agenda. Out of those opinions, this subcommittee reached
several conclusions. In our report we made several recommenda-
tions about the future research agenda and the coordination of re-
search efforts by all agencies involved. Essentially, we are here
today to determine whether the Research Working Group has im-
plemented those recommendations and how we can help in assur-
ing the implementation of our suggestions and the overall success
of the research effort.

Mr. Chairman, I look forward to hearing from these outstanding
witnesses about this very serious matter that we need to spend a
lot of time on to make certain that we get to the bottom of it as
fast as we possibly can. Thank you, and I yield back.

Mr. Suays. I thank the gentleman. At this time I recognize the
gentleman from Maine. We are catching you just as you walk in
here, but would you like to make a statement?

Mr. ALLEN. Very briefly, Mr. Chairman. I just want to say how
much I appreciate your leadership on this particular issue.

This subcommittee reported last fall that, in our view, the Fed-
eral Government has failed to address the chronic ill effects which
have disabled and compromised the health of thousands of our Gulf
war veterans. A coordinated effort in addressing the neurological
disorders afflicting a growing number of servicemen and women
who served in the Gulf war theater is critical, and I look forward
to today’s testimony by the Research Working Group and the Gen-
eral Accounting Office on what measures the Federal Government
has taken to coordinate research efforts and the effectiveness of
those efforts. I am particularly interested in learning how the Re-
search Working Group is responding to the recommendations made
by this committee.

Thank you very much, Mr. Chairman. I yield back.

Mr. Suays. Thank you, Mr. Allen.

Just to get some housekeeping out of the way, I would ask unani-
mous consent that all members of the subcommittee be permitted
to place any opening statements in the record and that the record
remain open for 3 days for that purpose.

Without objection, so ordered.

I ask further that all witnesses be permitted to include their
written statements in the record.

Without objection, so ordered.

At this time I will call on our panel: Dr. John Feussner, Chief
Research and Development Officer, Department of Veterans Af-
fairs, accompanied by Dr. Timothy Gerrity, Special Assistant to the
Chief in the Research and Development Office, Department of Vet-
erans Affairs. Second is testimony from Dr. Anna Johnson-
Winegar, Director of Environmental and Life Sciences, Department
of Defense. Dr. Drue Barrett from Environmental Hazards and
Health Effects Division, Centers for Disease Control and Preven-
tion. Also accompanied, not giving testimony but here to respond
to questions in her soft voice, Dr. Sheila Newton.

So we will have testimony from three and we will have five par-
ticipate in the dialog. I want to just call you all doctors now. Since
my wife is seeking her doctorate, I know what it involves, and so


182

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110

MWDs receive semi-annual physical examinations throughout their active duty
lives, which include clinical evaluations and routine panels of hematologic, serologic,
and blood chemical analyses. The results of these tests are recorded in the animal's
medical record. Those MWDs that are euthanized will have peripheral blood samples
collected prior to euthanasia for the above tests. When natural death occurs, the most
recent blood test will be used. Test results are to be included in the dog's permanent
medical record. Necropsies are performed in accordance with a standard protocol
contained in TB Med 283. Medical records from all deceased MWDs in the Department
of Defense are archived at the DODMWDVS, Lackland AFB, Texas.

Based on the assumptions of a condition with 10% prevalence in the population,
looking for a relative risk of 2.5 in the exposed group, setting the alpha level at 0.05 and
the beta level at 0.2, a minimum of 112 animals of each group must be included in the
study. Therefore, the medical and training records of those 118 MWDs which deployed
to the Persian Gulf, and 472 non-deployed MWDs matched four to one based on age,
gender and breed, will be abstracted during the study period for the following variable
animal identification; age at death; date of death; breed; gender; location during the time
frame 1 August 1990 to 31 December 1991; duration of deployment; neurologic iline:
orthopedic illness; dermatological illness; gastrointestinal illness; infectious diseases;
parasitism; neoplasms; behavioral changes after 1 August 1990; pathologic diagnoses
of biopsy specimens and pathologic diagnoses of autopsy specimens. These data will
be electronically stored in a database for statistical analysis using the SPSSp analysis.
program.

Those 30 Persian Gulf deployed MWDs still living, and 120 age, gender, breed
matched non-deployed control MWDs will be transported to the DODMWDVS, Lackland
AFB when the responsible Veterinary Corps officer has determined the animal is no
longer physically fit for duty and in need of humane euthanasia. Upon arrival, the
medical record will be screened to determine the cohort of assignment. The MWD will
receive a complete physical exam, to include the following: CBC; serum chemistry
panel; serum acetylcholinesterase activity levels; urinalysis; fecal exam for parasites;
canine thyroid hormone measurements (Ts, TSH); electrocardiography; radiography; a
neurologic examination and a behavioral assessment.

The MWD will be anesthetized according to a standard approved protocol.
Radiographs of elbows, stifles, coxofemoral joints and spine will be obtained if not
present in the record. Electromyograms and nerve conduction studies will then be
conducted on the anesthetized dog, to determine neuromuscular function.

Euthanasia of the dog will be completed with a standard approved injectable
‘euthanasia agent (Beuthanasia) and immediately necropsied in accordance with the TB
Med 283. At necropsy, gross changes are described and an extensive set of tissues.
collected and forwarded to the Department of Veterinary Pathology, Armed Forces
Institute of Pathology, Washington, D.C. Muscle biopsies of the biceps femoris and
triceps brachii; and nerve biopsies of the tibial and radial nerves will be collected for
analysis at Auburn University. Additionally, 6 gram samples of liver, kidney, lung, brain
and fat will be collected for ultra low temperature freezing and stored at the AFIP or
DoD Veterinary Laboratory until toxicological procedures may be performed, if
indicated. Formalin fixed tissues will be processed for histopathologic examination
resulting in a detailed final pathology diagnostic case report consisting of a list of



69

Secretary of Health and Human Services, and other officials to meet the prime
objective in military or civilian terrorism exigencies that may_arise in the near term.

Attached are DoD responses to the questions posed in the Federal Register
notice. Also, to supplement the public record, we resubmit our comments of
September 13, 1996, and enclose a copy of the 1996 testimony of Dr. Edmund Howe
to the Presidential Advisory Committee on Gulf War Illnesses concerning the ethics of
the military combat exigency rule.

Thank you for your assistance in these matters over the past few months and for
your consideration of DoD comments on this important national security issue.
Sincerely,

Eater Maile

Edward D, Martin, M.D.
Acting Assistant Secretary of Defense

Attachments:
1. DoD comments on questions posed in Federal Register notice.
2. DoD letter to FDA of September 13, 1996.
3. PACGWI 1996 testimony of Dr. Edmund Howe.


2

CONGRESSIONAL TESTIMONY
GULF WAR VETERANS’ ILLNESSES

Tatroduction

‘Mr. Chairman, thank you for the opportunity to review with you and the members of this
important subcommittee the current and projected DoD research program addressing multiple
aspects of Gulf War Veterans’ Ilinesses (GWVI).

Tam Dr. Anna Johnson-Winegar, Director for Environmental and Life Sciences (DE&LS),
Office of the Director of Defense Research and Engineering (ODDR&E). As the DE&LS, I
oversee the Defense biomedical and medical science and technology program. Today, I will focus
my testimony on GWVI research matters.

Department of Defense Oversight of GWVI Matters

In overseeing the Defense biomedical and medical science and technology program, I am
accountable to the DDR&E. As you know, the DDR&E is the principal staff assistant and
advisor to the Under Secretary of Defense for Acquisition and Technology (USD(A&T)) for DoD
scientific and technical matters, basic and applied research, and advanced technology. Health
policy issues and activities as they relate to the Department's readiness mission are the
responsibility of the Assistant Secretary of Defense for Health Affairs (ASD(HA)). This mission
includes providing medical services and supporting U.S. Forces during military operations, as well
as providing medical services and support to U.S. Forces, their dependents, and others entitled to
DoD medical care. The ASD(HA) reports to the Under Secretary of Defense (Personnel and
Readiness) (USD(P&R)). The USD(P&R) is the principal staff assistant and advisor to the
Secretary and Deputy Secretary of Defense for Total Force management as it relates to readiness,
National Guard and Reserve Component affairs; health affairs, training, and personnel
requirements and management, Operating independently of these USD(A&T) and USD(P&R)
program responsibilities is the Office of the Special Assistant for Gulf War Illnesses (OSAGWI)
‘The OSAGWI is developing case narratives, studies and models to better understand and resolve
exposures during Gulf War service.

also serve as the Chair of the Armed Services Biomedical Research Evaluation and
Management (ASBREM) Committee. It is co-chaired by the Deputy Assistant Secretary of
Defense for Health Services Operations and Readiness, Office of the ASD(HA). The ASBREM
Committee provides centralized management for the Defense biomedical research, development
and acquisition (RDA) program. This program includes medical chemical defense, medical
biological defense, infectious diseases of military importance, military operational medicine,
combat casualty care, and radiological defense, as well as congressional special interest
biomedical RDA efforts. It involves the discovery, development and acquisition of the means—
knowledge and technology-to prevent and treat disease and injury through biomedical solutions
to operational health threats posed to U.S. Forces. Biomedical solutions include pharmaceuticals,


143

Mr. SHays. Well, we can’t get into the issue of the studies, but
I have a feeling that you are aware that the studies go into more
than whether they fit properly.

Ms. WineEcar. Yes, that is correct.

Mr. SHays. And the question I am asking is should someone like
Dr. Feussner and Dr. Barrett and Dr. Newton and Dr. Gerrity,
shouldn’t they be aware of these studies? Do you all have a security
clearance?

Ms. BarrETT. No.

Dr. FEUSSNER. No, sir.

Mr. GERRITY. No, sir.

Mr. Suays. You don’t have security clearances?

Dr. FEUSSNER. No, sir.

Mr. SHays. You see, my problem is there are studies out there
that I think people should get and see and evaluate, and you are
not even allowed to see them. I find that incomprehensible.

Let me take one more line of questioning and then we will get
to you again, Mr. Sanders.

ere is a question on whether our studies have not been focused
too much on trying to find the smoking gun, even if it is chemical,
and that it should be more focused on treatment and treatment
outcomes. Dr. Feussner, why don’t you respond to that.

Dr. FEUSSNER. Well, I’ve indicated before that we have program
announcements that are open-ended to solicit research for treat-
ment trials. We have convened a planning group to plan a trial in
the area of chronic fatigue syndrome and fibromyalgia. We are
quite receptive to trying to plan an antibiotic trial, and Mr. Sand-
ers has volunteered to help me with that. And we have treatment
trials under way, at least one treatment trial under way for

sttraumatic stress disorder that we began in, I believe, June or

eptember 1996. The reason we released the program announce-
ment was to make it clear that there is essentially an open-ended
solicitation for treatment trials. We made the criteria for those
trials, I think explicit.

The way that VA would typically go about planning these trials
is we would convene a planning committee that would bring in
whatever expertise is required to plan the study; we would assign
it to one of our coordinating centers. We have four such centers
around the country who would facilitate the methodological, statis-
tical, and data management issues. The completed proposals then
are submitted for peer review by our Cooperative Studies Evalua-
tion Committee. If they are approved, then we would initiate them.

So that is the process that exists. The program announcement
opens the door, in my view, to trials, at least on subsets of patients
who can be defined. As I said earlier, they require that the patients
be definable, that the treatment protocols be replicable and explicit,
and that the outcome measures be credible. Other than that, I
think it is an open opportunity.

Mr. SHays. But do you think that most of our research is more
toward trying to find the cause and less—or more on trying to find
treatment and focusing on treatment outcomes?

Dr. FEUSSNER. I think that we have not had research efforts to
systematically approach treatment issues.

Mr. SHAYS. So we need to do more on that?


10

engaged to ensure that each department participates in discussions on the issues. A
specific example of this is when DoD made its determinations about the potential for
exposure of troops to nerve agent at Khamisiyah. The determination was made through
the work of DoD’s Office of the Special Assistant for Gulf War Illnesses. However, DoD
immediately engaged the RWG to develop a coordinated research response to this event.
The RWG response was the development of an action plan that led in part to the
development of DoD’s 1997 Broad Agency Announcement requesting new research on
the health effects of low-level exposure to chemical warfare agents and environmental
toxins, alone and in combination with one another.

‘The RWG has guided the federal research portfolio using a number of different
sources of input. These sources include results from ongoing research; various expert
panels and oversight committees, such as the Institute of Medicine, the Defense Science
Board, the National Institutes of Health; Congressional committees including the Human
Resources Subcommittee; the Presidential Advisory Committee on Gulf War veterans’
illnesses; independent scientists; and veterans. The RWG has synthesized the advice and
information into a research strategy embodied in A Working Plan for Research on Persian
Gulf Veterans Mlnesses first released in August 1995 and revised in November 1996. The
next revision will be available later in Spring 1998.

Other notable activities and accomplishments of the RWG include:

‘Production and dissemination of Annual Reports to Congress on progress and results
of federal research activities;

© Secondary programmatic review of research proposals submitted to funding agencies;


141

Mr. SHays. DOD? I am really asking for the record.

Ms. WINEGAR. To the best of my knowledge, they did not test.

Mr. Suays. There was no testing. We had soldiers who described
pretty horrific experiences. Soldiers telling us what they described
to their doctors: alarms went off, SCUD missiles came in; alarms
went off, we went undercover, into the bunker; alarms went off,
going on, rather, and then the signal that the coast was clear. They
came up, they tasted, they smelled, they spit up blood, threw up
and had rashes, and ran down. They testified to that under oath.
They testified that they told the VA doctors that.

What-—why—I don’t need to ask that question. I don’t want to
go over the past in that sense. What I want to go over is just the
fact that it is established that the VA didn’t respond and make any
assumptions that it might be chemical exposure, in spite of the fact
that Saddam Hussein had chemicals and used them on civilians
and Iranians.

My question is this: What test did the VA do to see if our troops
were exposed to chemicals? Dr. Gerrity. The DOD didn’t test.

Mr. GERRITY. Certainly by the time soldiers were coming back to
the United States, there would be no tests that could adequately
measure levels of exposure to sarin. However, the Department of
Veterans Affairs did establish a clinical program focusing on neuro-
logical outcomes at the Birmingham VA, looking specifically at the
question of whether or not veterans may have been exposed to
chemical warfare.

Mr. Suays. I thought they were. The problem was that we didn’t
really do—we didn’t have in the protocol early on to even ask them
about chemical exposure. Specifically, we had it in places like New
Haven—excuse me, West Haven—because one of the doctors at the
VA was an environmental scientist from Yale who had some exper-
tise, so he introduced some questioning.

The point I am trying to get to is this: We didn’t—it is my under-
standing that—so correct me if I’m wrong—that if we don’t—that
some chemicals you can’t detect even early on for chemical expo-
sure; others you can early on. But in many cases, the longer time
that passes, the more difficult it is to detect chemical exposure.
Now they may have the effects of chemical exposure, but you can’t
detect the chemical, is that correct?

Mr. GERRITY. That is correct.

Mr. Suays. So the challenge, it seems to me in our protocol now,
is to—and it is even more so with biological agents is this right,
Dr. Barrett and Dr. Newton, or Dr. Fuessner? Biological exposure.
You wouldn’t know that there was a biological agent out there pro-
viding exposure, would you, at low level?

Ms. WinEGaR. I think the converse is true. Quite often, exposure
to a biological agent leads to a specific antibody response that may
last for quite some time, whereas that is not true for exposure to
chemical agents, simply because of the amount of material re-

quired.
Mr. SHAYS, So it is easier to detect biological exposure, low level?
Ms. Winecar. In people that have been exposed, I believe so, yes.
Mr. SHays. Would that be the testimony of all of you? Dr. New-
ton.


184

Although much remains unknown about these symptoms and conditions, several
irrefutable facts that have emerged. The first is that there is not one unique or discrete
illness that occurred in veterans deployed to the Persian Gulf. Instead, these
individuals suffer from the same patterns of symptoms that afflict millions of Americans,
and go by numerous semantic terms such as Fibromyalgia, Chronic Fatigue Syndrome,
Multiple Chemical Sensitivity, etc. Also, some individuals with these symptom
complexes are inappropriately labeled as having a psychological problem. These
problems with overlapping symptoms and syndromes, and the inappropriate psychiatric
attribution of symptoms, occur whether these individuals are seen in VA or military
facilities, or in the private sector. The important issue in this regard is that the lack of a
single definition for these illnesses, or of any laboratory or diagnostic tests that can
definitively establish the diagnosis, causes considerable problems in researching these

conditions.

The second important point is that these conditions historically have received
very little research attention. In contrast to illnesses such as cancer and infectious
diseases, which have been well-funded, well-researched, and are well-understood, our
baseline state of knowledge regarding the physiologic mechanisms and treatments for

these types of conditions is primitive.

The final important aspect about these illnesses is that the same exact symptom

complex can be triggered by many different factors. Most are aware of the debate that


© the relative order of merit,
'* regulatory compliance;

© the availability of funds; and
‘© project affordability.

One of three different types of awards may be made. The most common is a cost-
reimbursement type of contract that permits reimbursement for actual costs incurred in the
accomplishment of the research. These contracts also permit some flexibility in the redirection of
research effort as a result of research findings or changes in program emphasis. Grants and
cooperative agreements may be used when the primary intent is to provide resources to support
and stimulate research. Additionally, grants are used when involvement and interactions between
Defense and the recipient are intended to be few; cooperative agreements are used when
‘substantial involvement and interactions are anticipated. The normal period of performance for an
award made under a BAA is 3 to 5 years.

GWVI Broad Agency Announcements. The majority of GWVI awards have resulted from
DoD solicitations using specific purpose announcements, Special funding opportunities are
normally announced by a BAA having specific closing dates for receipt of proposals and usually
do not encourage use of the preproposal process. Proposals must be responsive to the
USAMRMC BAA 95-1 requirements as well as to any special provisions of a specific
announcement. The DoD, through USAMRMC, has advertised seven GWVI special topic BAAS
since 1994, The most recent, FY98 Gulf War Illness Research Program, was announced on
November 20, 1997 and closed February 4, 1998. To date, these seven announcements have
resulted in 29 awards. The number of proposals and awards in response to BAA by year are as
follows:

GWVI BAA SUMMARY (FY94 - Present)

Date of ‘Special Proposals | Awards To

Announcement Solicitation Topic Received Date
29 Apr 94 Low level chemical sensitivities 3 1
29 Apr 94 Depleted uranium 2 2
24 May 95 Gulf War Iliness, 3 subtopics 7 14
10 Dec 96 Low-level chemical exposures 22 4
29 Jan 97 Gulf War Illnesses (non-Federal) 36 8
29 Jan 97 Historical War Syndromes 14 3 (pendin,
20 Nov 97 Gulf War Ilinesses (non-Federal, US. 4 BAA closed
universities) on 4 Feb 98.

Since 1994, the DoD has awarded funds for 35 (this includes both the open-ended and special
funds BAAs) extramural projects intended to improve our knowledge and understanding of the
pathogenesis of GWVI. At present, there are additional extramural projects undergoing review or
negotiations for award.


166

Of the information for improving understanding of the patterns of
veterans’ complaints. These data limitations were unfortunate, as
detailed information about symptoms and exposures might have
yielded earlier, more reliable analyses of the nature and causes of
veterans’ complaints and could have also assisted in developing

working case definitions.

We also found that both the federally supported projects and the
federal registry programs have generally failed to study the
conjunction of, multiple symptoms in individual veterans. Articles
and briefing documents that we obtained from DoD and VA reported
findings that addressed only the incidence of single symptoms and
diagnoses. There were two exceptions. First, for an Air National
Guard unit in Pennsylvania, the Center for Disease Control and
Prevention developed an operational case definition, which was
quite similar to the case definition of chronic fatigue syndrome.
Second, the studies conducted by Haley et al. also focused on

identifying symptom clusters.

For those ongoing, epidemiological studies that were built on case-
control designs, we asked about how a case was defined. The
specificity of this definition is important because a vague case
definition can lead to considering multiple kinds of illnesses
together. When this is done, it is not surprising to find no
commonality of experience among the cases. Moreover, the use of

specific case definition is particularly critical to achieving

18


186

would be foolish for the CDC, arguably the world’s finest epidemiologic research
organization, to extensively out source this type of work. In contrast, the Department of
Defense does not have as much intemal expertise with these types of illnesses, and
has been aggressive in funding investigators outside the government, as well as in
stimulating and directing its own researchers in new directions. The VA has likewise
decided to capitalize on its strengths, including one of the world’s best organizations for
performing multi-center treatment trials. They have asked me and others outside the
VA who have expertise in these illnesses to help design a large treatment trial for
persons with these illnesses. This project is undoubtably the largest single clinical trial
in this type of illness, and in fact the amount of money set aside for this effort by the VA
Probably exceeds the total amount spent on ai! treatment trials ever performed on

these illnesses.

| was also asked to specifically comment on the procedures used to evaluate,
review, and fund research proposals. Although | do not know the precise mechanisms.
which have been used, the peer reviews of my two grants were every bit as critical and
stringent as for NIH grants | have submitted. In fact, the DOD even took the unusual
step of asking the principal investigators of Gulf War projects to modify their protocols
in response to the peer review comments. This extra step further strengthens the
scientific integrity of the protocols, and is more stringent than the post-review process

for funded NIH or NSF grants.


98

of providing ethical input to the DOD. This process ‘consisted of
many hours of discussion at multiple meetings held by the DOD with
the OPRR and other experts, including those from other governmental
agencies such.as.the FDA. I was fortunate enough to be one of the

civilians asked to participate in this process.

The ethical questions posed were of enormous significance
because in addition to servicepersons' autonomy, tens of thousands
of servicepersons' lives were potentially at stake. It was known
that certain agents would help protect servicepersons from the
harmful effects of these weapons if Iraq chose to use them. Thus
the use of these agents, literally, might have been lifesaving.
Yet, these agents had not been tested for this particular use on
humans. It would, in fact, have been unethical to subject humans
to the effects of chemical or biological weapons to determine the
extent to which these protective agents would be effective. Thus,
two unprecedented ethical questions arose: Should these agents be
used at all? And if they should be, should servicepersons be given
the opportunity to withhold consent?

The ethical justification of the military's giving
&ervicepersons these agents without obtaining their consent is as
follows: For the sake of this discussion, it must be assumed that
this war was both necessary and just. If this is assumed to be
true, servicepersons have unique obligations during war both to
their country and to other servicepersons with whom they risk their
lives during combat. That is, servicepersons agree to sacrifice

their lives if necessary to further the military's mission or to


140

rate incidents from Beople with FOX equipment who said that we
detect it with our FOX equipment, well-calibrated equipment. And
then their superiors say, “well, they were mistaken.” They were
trained to do this, and they said that they were mistaken. So we
just become very suspicious.

I wondered, Mr. Gerrity, how do we detect—Dr. Gerrity, I am
sorry—how do we detect chemical exposure on the body?

ir. GERRITY. There are a number of ways to do it depending
upon what the chemical is, and so it is highly chemical specific.
And some chemicals are very, very difficult to detect on the body.

Mr. SHAYS. Very difficult to detect?

Mr. GERRITY. Are very difficult to detect, especially after the ex-
posure has occurred, because they may disappear rapidly from the

ody. For example, volatile organic compounds, because of their na-
ture, tend to be expired through the breath and leave the body, so
that hours, days later, you won’t be able to detect them in the
blood. However, there is a lot of research that is going on at EPA,
and at the Centers for Disease Control and Prevention, trying to
develop ways to relate the chemicals that we can measure in
human bodies to atrial exposures that may have occurred but left
to those body burdens.

Mr. SHays. So your testimony would be if you don’t detect it
right away, it is unlikely you are going to detect it?

ir. GERRITY. Oh, no. It is highly chemical dependent. There are
some chemicals, for example, that are highly fat soluble, that you
can detect years after.

Mr. SHays. So some you can detect years after, but some you
can’t. How about the chemicals that Saddam had?

Mr. GERRITY. For example, sarin?

Mr. Suays. I am curious to know what you know he had.

Mr. GerRITY. Sarin is an anticholesterase agent. It binds up with
acetylcholine and in a matter of days after an exposure, your levels
of acetylcholine approach normal. The marker there is—actually,
your level of acetylcholine is the marker of exposure. Now, there
are research efforts that are going on——

Mr. Suays. So in sarin, if you don’t detect it fairly quickly, it is
very difficult to detect?

Mr. GerRriTy. Sarin is very difficult to detect. Research funded by
the Department of Defense, that was just recently published, from
working on other ones where they have been able to look at the
amount of sarin in Japanese victims of both Matsumoto and——

Mr. Suays. But the bottom line is if you don’t detect them quick-
ly, then you are likely not to be able to know?

Mr. Gerrity. Again, it is chemical dependent. But for sarin, that
is true. I think one of the things, though, is that what we would
like to know is whether—and we have asked for continued develop-
ment on this—there are surrogate markers that might last longer.

Mr. Suays. Right. Just memory loss and other things that relate
to—but what I am interested to first establish is that DOD didn’t
test our soldiers right after the war, did they, or during the war?
They didn’t test them. They came in and said the alarms are false,
the FOX equipment is false and they didn’t test. That is a fact,
isn’t i

Mr. GerriTy. You would have to ask that of DOD.


91

13

approved treatment protocol reached the Gulf, the Central Command
changed the protocol. It was modified (without notice to the
Pentagon, as far as can be reconstructed, until after the
fighting stopped) to permit members the choice of declining the
vaccine. The Central Command Surgeon recently explained the
change as being based on three primary factors:* 1) very limited
vaccine supply; 2) the lack of intelligence reports that would
have allowed prioritized use of the limited supply based on some
judgments that certain personnel are more at risk than others; 3)
Command concerns about rumors arising from a Stare and Stripes
article reporting on allegations back home about requiring troops
to take “experimental vaccines." Anecdotal reports leave
somewhat unclear whether, in actual use throughout the theater of
operations, the vaccine was uniformly administered in accordance
with the Central Command's revised protocol or was sometimes
given consistent with the original protocol.

The Central Command's revision to the protocol was a
surprise to the DoD officials with whom the FDA was dealing.
But, in retrospect, it was quite proper to give the responsible
military command the option to decide whether actual military
circumstances unfolding in the theater of operations truly
required the standardized use of the vaccine. Had intelligence
reports changed or had the timetable for combat operations
allowed for procurement of additional supplies, implementation of
the original protocol might have been necessary after all. It
was not unreasonable to give the Central Command that option.
However, there was a breakdown in communications that prevented a
common understanding among all involved officials. Had
communications been better, the determination that informed
consent was not feasible could have been contingent upon a final
Command decision confirming the existence of, in the words of the
rule, “special military combat (actual or threatened)
circumstances" which “require that a particular treatment be
provided to a specified group of military personnel, without
regard to what might be any individual's personal preference for
no treatment or for some alternative treatment."

* Testimony of Brigadier General Robert Belihar before
Presidential Advisory Committee on Gulf War Veterans' Illnesses,
Public Meeting, Kansas City, Missouri, January 12, 1996.


193

ment protocols, because after all is said and done, ultimately what
we are dealing with is 70,000 to 100,000 people who are hurting,
and we want to make them well.

I know the last time you were here, Dr. Haley, you were pessi-
mistic that some of this damage may be irreparable, as unpleasant
as that may be. Others may disagree with you. Why don’t we start.
with you again and tell me, at this point are you comfortable with
any treatment protocol that could improve these symptoms? What.
do you think?

Dr. HALEY. If it is neurological, neuronal damage, chances are
you can’t cure it. However, that damage in the brain stem and sub-
cortical areas typically produces demonstrable changes in nerve
function in the body. For example, the sympathetic nervous system
may become hyperactive and so forth. These systemic manifesta-
tions, if we understand what they are, probably can be interrupted
and made better.

For example, one of the things we are now noticing, now that I
really know how to take a history in a Gulf war veteran, which I
didn’t know up until a year or two ago, often they describe two dif-
ferent components to their symptoms. There is a sustained compo-
nent which is the cognitive problem. Those tend to be the same all
the time. But the muscle aches, the systemic symptoms, those tend
to come and go. You hear veterans say, I have good days and bad
days. Things that come and go probably can be interrupted, and if
we could interrupt those, most of these Gulf war veterans would
really be happy. So I think there probably are medications. It is a
matter of identifying them in good studies.

The key is, though, there must be a Gulf war specific case defini-
tion, and if you don’t do that, you are going to be lumping people
with this Gulf war related neurological problem with a whole
bunch of other people and people who don’t even have anything,
and then the treatments, you are not going to show whether they
work.

Mr. SANDERS. The bottom line of what you are saying is that the
better we understand the cause of the problem, we can in your
judgment make progress treating, significant progress, perhaps, in
alleviating the symptoms?

Dr. HALEY. Right. I go back to my colleagues at GAO here. Read
my lips. Case definition. There must be a case definition of the Gulf
war syndrome. Otherwise, all the treatment trials are going to be
like the three New England Journal studies; we are going to see
no difference, because we are lumping things together that don’t
belong together.

Mr. SANDERS. Dr. Clauw, could you respond to that also?

Dr. CLauw. I generally agree. Maybe I am even more optimistic
that many of these conditions can be treated, and again, that is an
area that needs intensive study.

Mr. SANDERS. Do you, Dr. Clauw, want to comment at this point
on any treatments that you have seen out there, perhaps using
antibiotics and so forth, as perhaps promising immediate hope?

Dr. CLauw. I think there may very well be a subset of people
with this whole spectrum of illness, again, not necessarily just Gulf
war illness, but chronic fatigue, fibromyalgia, multiple chemical


i

‘© Presentations by federal and non-federal researchers before the Research Working
Group;

‘* Organization of meetings of federally-funded researchers;

‘Organization of an international symposium in conjunction with the Society of
Toxicology on the health effects of low-level exposure to chemical warfare nerve
agents.

* Development of a strategy for research on the health effects of exposure to low-levels
of chemical warfare nerve agents.

© Follow-up investigation of preliminary reports of positive experimental serological

tests for leishmaniasis.

I want to highlight some of the ongoing research efforts on Gulf War veterans’
illnesses.

Shortly after the June 1996 announcement of the events at Khamisiyah, the
Research Working Group acted to recommend funding by DoD of three proposals that had
been previously deemed scientifically meritorious but not funded. The three projects are
valued at approximately $2.5 million and involve (1) dosimetry research on exposure to
sulfur mustard that will enable quantitative determinations of sulfur mustard exposure at
short and long-term intervals; (2) research on the toxicokinetics of the nerve agent VX in
three species of animals. The results of this research will facilitate animal to human
extrapolation of observed effects in animals resulting from controlled low-level nerve
agent exposure; and (3) research on the role of genetic expression of cholinesterases in

protecting against anticholinesterase nerve agents. Each of these are described in more


97

USE OF INVESTIGATIONAL DRUGS AND VACCINES IN THE GULF WAR

ETHICAL CONSIDERATIONS IN WAIVING INFORMED CONSENT
FOR MILITARY EXIGENCIES

Mr. Chairman, distinguished Members of the Committee, I am
Edmund G. Howe, M.D., J.D., Professor of Psychiatry and Director of
Programs in Medical Ethics at the Uniformed Services University of
the Health Sciences. I appreciate the opportunity to discuss with
you today the exceedingly difficult ethical questions which arose
in regard to the use of protective agents in the Persian Gulf.
When the DOD first anticipated that Iraq might use chemical and
biological weapons, the DOD was aware of the profound ethical
dilemmas this situation posed. Consequently, the DOD immediately
sought consultation from other governmental agencies and civilians

outside the DOD with special expertise in medical ethics.

One of the parties with whom the DOD conducted extensive
discussions was the Office for Protection from Research Risks
(OPRR/NIH). The OPRR is responsible for monitoring and protecting
the health and welfare of humans and animals when they are used as
research subjects in behavioral and biomedical research supported
by the Public Health Service. Guidance from the OPRR was
particularly valuable to the DOD's understanding of the ethical
issues involved pertaining to research. The OPRR pursued extensive

ethical discussions with civilian ethicists throughout the process


187

Although | feel that the federal research effort to date has been appropriate, |
have several comments and suggestions regarding the future direction of these
endeavors. First, we must acknowledge that we will likely never know precisely what
caused Gulf War illnesses. It has become clear that there was inadequate information
collected on Gulf War veterans’ pre-deployment health, and on their potential
environmental exposures and stressors, to learn precisely what made certain
individuals ill, But we still have ample opportunities to learn about the causes of these
symptom complexes. Nearly all of the environmental exposures suspected to cause
Gulf War illnesses also occur in the general population. Some individuals exposed to
physical trauma, emotional stress, infections, drugs, toxins, and other types of stressors
develop these chronic nonspecific symptom complexes, whereas many others do not.

These individuals and the illnesses they develop need to be more extensively studied

But even if we do not know precisely what caused Gu!f War illnesses, we must
proceed with aggressively pursuing research focused on the treatment of these entities.
Most who have studied these syndromes agree that although there may be many
different types of triggers of these conditions, once someone develops one of these
illnesses, the treatments are very similar. My opinion is that we have all been
somewhat paralyzed by this need to know what caused Gulf War illnesses, and that we

must aggressively move forward in pursuing treatment programs

Lastly, | feel that further research into the causes and treatments of these


102

for the agents considered, the probable benefits were overwhelming
and the expected adverse risks, minimal. If this had not been the
case or if the benefit/risk ratio had even been significantly
closer to marginal, the justification for using these agents would
have been, of course, increasingly problematic.

Second, it can be argued that even if these agents should be
available, servicepersons should be able to refuse to take them. If
servicepersons could refuse consent, this would respect their
autonomy, but several important values would be violated. That is,
if servicepersons were permitted to refuse to consent, two options
would be possible: Servicepersons who refused consent could be
excused from combat altogether or they could remain in combat
without their being protected by these agents.

If servicepersons were excused from combat, this could result
in US troops becoming significantly depleted. This could
jeopardize the success of the mission and increase the danger to
servicepersons who remained in combat. Further, if consenting
servicepersons remained in combat, this would violate the ethical
principle of justice or equity. That is, those who took the agents
would still risk being killed during combat by normal weapons;
those who did not take these agents and, therefore, were removed
from combat would not.

If, on the other hand, servicepersons who refused consent
remained in combat without these protections and Iraq used chemical
or biological weapons, the servicepersons without protection would
be much more vulnerable to illness and death. Again, as a result of

the depletion in their numbers, the success of the mission could be


201

you made recommendations in terms of the issue of improving and
monitoring clinical process, emphasis is needed.

Based on your statement, I was trying to get a sense of it and
it didn’t hit me the way I wanted. I wanted you to be more direct.

Do you feel that some of the recommendations you reported are
being implemented? Do you feel that it is being ignored? I want
you to be very specific.

Ms. HEIvILIN. I think the one on monitoring the treatments and
the effects of the treatments is being ignored.

Mr. Suays. Is what?

Ms. HEIVILIN. Being ignored.

Mr. Suays. And the other one?

Ms. HEIVILIN. The one to fund more low-level chemical research?
That is happening. There are three studies that have been funded,
but of course there was a congressional mandate that that was a
response to.

Mr. SHays. OK. Dr. Haley, I just also want to comment that
you—I have found myself trying to be responsible by saying there
is no one Gulf war illness, there are many, and there is no silver
bullet. So you kind of went after something that I need to think
about. You went after something that my colleague Mr. Sanders
also wrestles with, and that is multiple chemical sensitivity. I gath-
er you feel that the focus—that my saying that there are many ill-
nesses, is almost like what I say in my office that everybody is re-
sponsible, so no one is responsible.

Is that your concern, that by saying that there is multi-, that in
essence we don’t get an answer? I want you to kind of focus on why
you——

Dr. Hauey. Right. Here is the reason. We sent 700,000 people
over there, and when they come back 10 to 20 percent of them are
complaining with very similar symptoms. Granted, the symptoms
fit a spectrum. Not one guy has all of them. Now, maybe that is
just 50 different things, but why would we assume that? They all
went to the same place, they were exposed to the alarms going off,
which may be chemical exposures, the litany of things, chemical ex-
posures. I think it is very reasonable to entertain the idea that this
is one injury, a subcortical brain stem injury that produces symp-
toms. It may be that that is what is involved with chronic fatigue
syndrome and multiple chemical sensitivity and fibromyalgia. In
fact, the most recent review on fibromyalgia says there is nothing
wrong with muscles, it is probably a neurological problem.

Mr. Suays. I hear where you are coming from, and I would say
that it is good for you to do that, but I wouldn’t think it would be
good for all of us to make an assumption that there is just one. I
mean——

Dr. HALEY. Let me say, in saying that, then I also have to point
out that in addition to the people that I think have this one illness
that has maybe some subcomponents or variants, one illness with
several variants, in addition, there are another 200,000 veterans
who have all kinds of things that you and I have that are normal,
and that is what the CCEP has focused on.

Mr. Says. But I think it would be a shame if your view was ig-
nored, because you may be right. But conversely, I wouldn’t reverse
it to say that only your view should be looked at.


192

I have AIDS or not, whether I am HIV positive. What I think the
chairman and I were trying to get at, what kind of physiological
tests are available, or might you use, which suggest that in the
broad sense, look, I can show you, young man, that you have Gulf
war illness? Can you talk about that point for a moment?

Dr. HaLey. As I mentioned, we published a study comparing
carefully selected cases and controls, we used audiovestibular tests,
evoked potentials——

Mr. SANDERS. You have to talk in English.

Dr. Hatey. Well, the problem is these don’t really have English
names.

Mr. SANDERS. What are these tests?

Dr. HALEY. For example, an audiovestibular test, one that we are
using now which we think is very sensitive, and potentially the test
is a test of what is called eye saccade, S-A-C-C-A-D-E. A saccade
is that little flicking eye movement. Let’s say something moves and

our eye just darts around, those little darting movements, the ve-
locity of that movement always is the same in every person. We see
that very regularly, Gulf war veterans who have the symptoms,
particularly what we call our syndromes 2 and 3, have slowed eye
movements or have a jerky eye movement or they have trouble ini-
tiating the eye movement.

There are similar other reflexes of the brain stem and the eyes
that can be tested by other very standard tests that have been used
for decades. The other set of tests, though, may be more sensitive
and we are experimenting with that right now, and that is tests
where you do clicks in the ear and then you measure with elec-
trodes on the side of the head and the brain, you measure different
spikes. As the sound or the stimulant goes into the brain stem, up
the brain stem, you get three major spikes. You measure how long
it takes the nerve impulse to get up the brain stem, and if this is
not the same on both sides, it indicates dysfunction of the nervous
system. These are the types of tests.

The grant that we are working with now is applying about 30
different tests to our cases and controls to try to work out which
ones would be most sensitive and specific to make the diagnosis.

Mr. SANDERS. All right. This is very important stuff, because you
are trying to give us some objective measurement for something
that we can demonstrably show. Let me just ask Dr. Clauw.

Dr. CLauw. I agree with what Dr. Haley says. I think there are
a number of tests that in many of these individuals with illnesses
will be abnormal, and I am glad Dr. Haley used the term dysfunc-
tion of the central nervous system rather than dementia, which im-
plies damage.

My only concern is that again, if he looks at the same types of
tests—we have done visual evoked responses and auditory evoked
responses in People with fibromyalgia and chronic fatigue syn-
drome—we find that a significant number of these individuals are
abnormal and they didn’t have these exposures.

Mr. SANDERS. OK. Let me go on to my next question, and I think
that that’s important information.

I am happy to be hearing today from the previous panel and
from the VA that there seems to be an increased focus and under-
standing that we need to move forward more vigorously on treat-


118

nel in the types of diagnostic tests that we employed to identify mycoplasmal infec-
tions of Gulf War patients. . .
et cetera.

In other words, it never ends.

What you are saying is, this guy may have a hypothesis. I think
what everybody here understands, we are not saying he is right,
we are not saying he is wrong, but for God’s sake the guy is on to
something. Are you going to come back next year and say, well, we
are going to continue to work with him?

We are spending millions and millions of dollars. He has a hy-
pothesis. Other people have hypotheses. They are people in the VA.

Now I would like to get on to this issue. Tell me, you are a doc-
tor, why would people—in terms of the whole issue of multiple
chemical sensitivity, do you believe in that?

Dr. FEUSSNER. Well, I don’t think it is an issue of belief. What
I will tell you is that I am very allergic to many of those things
personally, so that my wife does not wear perfume, my daughter
does not wear perfume, because I have a low tolerance for those
things.

What I will say is, as a very allergic individual, that I have reac-
tions to things that other people don’t. I treat that with avoidance.
I have treated that with immunotherapy in the past, and I am bet-
ter.

At any rate, I don’t know if that speaks to the issue of belief or
not.

Mr. SANDERS. I have taken too much time. My last question, Mr.
Chairman.

What would it tell you if you are sitting around a room of people,
all of whom were over in the Gulf war, and they all respond—they
get sick if they are around scented chemicals or they are around
perfume? Don’t you think there is a hypothesis there that we might
explore that suggests that these people have a chemical problem?

I failed biology actually in college, I must confess. I am not a doc-
tor, but it doesn’t take a genius to suggest that there may be a
problem here, that it is not an accident that so many people are
responding that way.

Dr. FEUSSNER. I think it is not an accident, and we are funding
research to further understanding in this area, yes.

Mr. SANDERS. You didn’t tell me whether you believe in the con-
cept of multiple chemical sensitivity.

Dr. FEUSSNER. Well, what I told you is that I get sick around
these things. What I am really interested in doing is not inflicting
my personal beliefs on others. I would like to generate some sci-
entific information that will convince my colleagues, who may or
may not be skeptical about this, that this is a reasonable consider-
ation. I think there are many examples of individuals who are al-
lergic.

Mr. Suays. Do you think it is a reasonable consideration?

Dr. FEUSSNER. Yes, sir.

Mr. Suays. I didn’t have my mic on, but the question was, “Do
you believe it is a reasonable consideration,” and the answer was

es”?

Dr. FEUSSNER. That's correct.


65

years, the RWG has had 12 to 14 presentations, including scientific
presentations, frequently from investigators who are not funded
through traditional Federal Government mechanisms.

Mr. Towns. I know it is difficult to predict exactly when we will
have information. Let me ask, can you give us some sort of esti-
mate about the amount of additional time we may expect these re-
search efforts to continue before we have some concrete answers?
I know you can’t be specific, but we are asked this question all the
time out there.

Dr. FEUSSNER. Yes, I am asked that question very frequently. I
don’t know the answer to that question. I view the research effort
as open-ended. Many of the research projects have only begun in
1993-1994, 1995-1996 timeframe. The research will not be coming
due until the turn of the century, 2000 and upwards. It really de-
pends on how insightful or how important the research findings
may be. A breakthrough could be discovered, or we may have to
stay at this research activity for decades.

I mean, there are analogies with other equally difficult clinical
problems. You probably don’t know, but insulin was discovered in
the decade of the 1920’s, and while we have been treating diabetes
aggressively with insulin, we, as yet, have no cure for that disease.

When my patients ask me why they have hypertension, I don’t
know in most cases what the cause of their hypertension is, al-
though I do have effective treatments. And in 1972, President
Nixon declared war on cancer, and a lot of research has been done,
a lot of progress has been made, but few cures pertain.

So I don’t know the answer to your question. We continue to con-
duct research today, for example, on Agent Orange exposures dur-
ing the Vietnam conflict. Our sense is that this is an open-ended
commitment.

Mr. Towns. Mr. Chairman, just one quick, last question.

Mr. Suays. Sure.

Mr. Towns. I think it was in September or October, the Food and
Drug Administration issued a notice requesting comments about
the advisability of the use of investigational drugs in a theater of
war. Did any of the agencies here submit written comments? What
was the essence of those comments, if you did; and will you submit
a copy of those comments to the committee, as briefly as possible?

Ms. WINEGAR. Yes. The Department of Defense did submit writ-
ten comments to that announcement, and we will be happy to
make a copy of those comments available to this committee also.
Basically, our concern dealt with issues that we would be faced
with should the interim rule be revoked, as has been suggested by
the FDA, and some of those deal specifically with the details of ad-
ministering those drugs by the Code of Federal Regulations re-
quirements, which include such things as obtaining written, in-
formed consent from each individual who would be receiving that
product and putting those in the context of a military operation.

We consider that the use of some of these materials is not really
a research project, because we are not there to actually gather
data; rather, we are there to provide these investigational mate-
rials as we believe that they are the best medical countermeasure


1

biological weaponry. The most important “experience in the Gulf War" was that the
enemy chose not to use this arsenal. If there is a basis for confidence that every
potential adversary in the future would also not use such weapons, then the rationale
for the military combat exigencies rule would not “still hold."

The problem is that the world community has clearly documented very
aggressive chemical and biological weapons programs in North Korea, China, Iran,
Iraq, Libya, Russia, and possibly other countries. In a future conflict, the United
States will have four options:

Option 1: To assume the enemy will not use chemical or biological
weapons, and, therefore, to eschew medical countermeasures.

Option 2: To excuse military personnel who chose not to use the medical
protection, both respecting their individual choice and saving them from danger.

Option 3: To allow individual military members to decide on the use of
medical countermeasures, but with the selection having no impact on the
individual's responsibility for the mission.

Option 4: To make standardized use of a drug or vaccine, when indicated
by the best evidence of its safety and efficacy, the degree of peril posed, and the
absence of a satisfactory alternative therapy.

The respective risks of each option must be considered. If option 1 is chosen,
and the assumption turns out to be wrong, there could be horrendous consequences.
Under option 2, the predictable consequences in any major scale military operation, are
a large number of abstentions, grave danger for remaining members who choose to
carry out the mission, and military failure. If option 3 is chosen and the enemy uses
chemical or biological weapons, those who declined medical protection will be at great
tisk, as will others in their units who rely on them and the accomplishment of the
aspects of the mission for which they were responsible. If option 4 is followed, and it
turns out that the enemy does not use the weapons, the drugs or vaccines would have
been received unnecessarily.

At this juncture, it is not necessary for the Secretary of Health and Human
Services to decide that option 4 is the most prudent course — only that it should be an
option; that it might be the best option under some circumstances that might arise. For
it to be an option, the military combat exigency rule must be maintained.

‘A.(4) Instead of waiving the requirement for informed consent, is it feasible to
obtain anticipatory consent from military personnel during peace time for the future use
of investigational products during a military conflict? If it is feasible, would such
consent be valid as “informed consent "? What would be the needed consent algorithm
to make it valid and feasible?


200

way, or at least that we are very actively trying to figure out what
to do to prevent it and what to do to treat it.

Mr. SHays. OK.

Mr. Cuan. Yes.

Mr. SHARMA. I agree.

Mr. Suays. Did you want to make a comment on an earlier ques-
tion?

Mr. CHAN. Well, the comment I would like to make is that there
were a number of studies they planned to do, particularly on low-
level chemical agents and other effects and so on. If indeed the hy-
pothesis that stress is one of the so-called important factors is true,

really would like to suggest then, that the research being done
should include stress as one of the dependent variables and con-
sider, that stress could be tiring or whatever. Certainly other coun-
tries have examined stress as a factor, including the PB people and
all the other agents that may cause the problem.

Mr. SuHays. You were pretty firm in your attack about stress
being a factor, and—not being a factor, excuse me, not being a fac-
tor—and it would seem to me that I would agree with your criti-
cism that the presumption that it is a cause is an outrage, but not
the effort to determine its role.

Dr. HALey. Here is my problem with it. It was never—it never
went through the stage of being a hypothesis. That is, we had 16
studies misapplying the Mississippi PDSD scale in which they
looked at some minor elevations and said, oh, stress. That became
accepted—it was a given then. It is no longer a hypothesis. That
is where it came from and that was totally fallacious.

Mr. Suays. But to the extent you mean that, I think you find
sympathy

Dr. HALEY. You see, I don’t know why we are treating this even
as an important contributing factor. There is no evidence. The only
study that has any merit, that is of any interest in my view, is the
Israeli study showing that physical—that is fear, I believe that is
what they studied—rats being thrown in water produces fear, and
that is what the model measures, that fear, fright that you are im-
minently dying, that you are on the way out, that mortal fear, that
may make the blood-brain barrier more permeable. That is a ve
interesting idea. Now, to translate that into the sorts of outlandis!
things that we are funding right now to look into stress and psy-
chological issues and all of this is, to my mind, bizarre.

Mr. Suays. I do know this. If I were a veteran and I came back
sick and I was told I had posttraumatic stress disorder, I would
want to punch someone in the face, and then I would probably be—
I would feel sicker. I mean it would make me sicker. Somehow just
having those who are trying to help me recognize that I am sick
and that I have a problem and I need their help and I want a little
sensitivity on the part of the people examining me would make me
feel a little better.

Let me just say, I am just interested in this one other area. You
wrote, in response to—not this committee, though we have pat you
to work on many occasions—to Senator Thurman and Floyd
Spence—well, actually, at the time they were the ranking minority
members on the Armed Services Committee—excuse me. Were
they? Excuse me. The chairman, and then to the ranking members,


16

5. VA issued a Program Announcement in August 1997 requesting proposals for
additional multi-center trials of PTSD treatment. Methodologies sought
include novel, non-pharmacologic approaches to treatment, with special
emphasis on targeted subpopulations such as women and Gulf War veterans.

I will now provide you with an update of the VA National Survey of Persian Gulf
Veterans authorized by Public Law 103-446. The Office of Research and Development
has awarded funds for Phase II] of the National Health Survey of Persian Gulf Veterans
and preliminary site selection has begun. A subcommittee of the Cooperative Studies
Evaluation Committee (CSEC, a federally chartered advisory committee), scientifically
reviewed the protocol for Phase III.

It is expected that physical examinations will begin in the near future. As you may
recall, the National Survey is designed to determine the prevalence of symptoms and
illnesses among a random sampling of Persian Gulf veterans across the nation. The
Survey is being conducted in three phases. Phase I was a population-based mail survey of
the health of 30,000 randomly selected veterans from the Persian Gulf era (15,000 Persian
Gulf veterans and 15,000 non-Persian Gulf veterans, males and females). The data
collection phase is complete and analysis of the data continues. Phase II consisted of a
telephone interview of 2,000 non-respondents from Phase I (1,000 from each group) to
determine if there are any response differences between respondents and non-respondents.
Additionally, 1,000 veterans from each group will be selected for a telephone interview to
validate their responses from the mail survey. Phase II is nearing completion. In Phase III
the 2,000 veterans who responded to the postal survey and underwent a telephone

interview will be invited, along with their family members, to participate in a


160

effects include difficulty in walking and paralysis. In recent
experiments, animals given a low dosage of the nerve agent sarin
for 10 days showed no signs of immediate illness but developed

delayed chronic neurotoxicity after 2 weeks.

It has been suggested that the ill-defined symptoms experienced by
Gulf War veterans may be due in part to Organophosphate-induced
Delayed neuropathy.'* This hypothesis was tested in a privately
supported epidemiological study of Gulf War veterans.’ In addition
to clarifying the patterns among veterans' symptoms by use of
statistical factor analysis, this study concluded that vague
symptoms of the ill veterans are associated with objective brain

and nerve damage compatible with the known chronic effects of

MK. Husain et al., "Assessing Delayed Neurotoxicity in Rodents
after Nerve Gas Exposure," Defense Science Journal, vol. 44 (1994),
pp. 161-164; K. Husain et al., "Delayed Neurotoxic Effects of Sarin
in Mice After Repeated Inhalation Exposure," Journal of Applied

, Vol. 13 (1993), pp. 143-145; and K. Husain et al., "A
Comparative Study of Delayed Neurotoxicity in Hens Following
Repeated Administration of Organophosphorus Compounds," Indi
Journal of Physiology and Pharmacology, vol. 39 (1995), pp. 47-50.

R. W. Haley et al., "Preliminary Findings of Studies on the Gulf
War Syndrome, * i

Advisory Committee on Gulf War Veterans’ Illnesses," September 16,
1995, and R. W. Haley, “Organophosphate-Induced Delayed
Neurotoxicity," i i

, October 10, 1996.
“This research, conducted at the University of Texas Southwestern
Medical Center, has been supported in part by funding from the
Perot Foundation.

12


99

benefit the servicepersons serving with them. Servicepersons
understand that they may have to sacrifice ‘any number of personal
interests during combat and, implicitly, they agree to make such
Sacrifices if this is necessary when they enter the military.

This shift from the usual ethical priorities adopted by
civilians during peacetime is exemplified by the principle of
military medical triage. Normally during emergency situations
medical careproviders give highest priority to saving the lives of
those patients who are worst off. During combat, military
physicians are expected under extremely rare circumstances to do
the opposite. Namely, they are expected to shift priorities and
treat servicepersons who are better off and can return to battle if
and when this seems necessary to further the likelihood of success
of the military's mission. In actuality, this hardly ever occurs.
In principle, however, this shift is radical. It is this same kind
of shift in regard to the use of protective agents which was
necessitated by the threat of Iraq's using chemical and biological
warfare against our troops.

The underlying ethical justification for this rare and radical
shift in priorities is that unless the customary values are
sacrificed, far greater wrongs may occur: these may include one
country taking over another and harming its people, genocide, and
even the destruction of this nation and its people. The different
priorities in the military during combat, accordingly, are not
established by the military but are established by and represent
the country whose interests it serves.

Servicepersons' priorities differ; then, from civilians’ in


21

Mr. SHays. Thank you very much. We will go to Dr. Winegar.

Ms. Winecar. Thank you, Mr. Chairman, for the opportunity to
review with you and the other members of your important sub-
committee the current and projected DOD research program ad-
dressing multiple aspects of Gulf war veterans’ illnesses.

As you indicated, I am currently the Director for Environmental
and Life Sciences within the Office of the Director of Defense Re-
search and Engineering. In this position I oversee all defense bio-
medical and medical science and technology programs. Today I will
focus my comments on our efforts on Gulf war veterans’ illnesses.

I want to emphasize at this point that the Department of De-
fense is committed to an aggressive, coordinated, well-focused, but
broadly scoped and strong Gulf war veterans’ illness research pro-
gram that does the following.

One, furthers the fundamental understanding of the illnesses;
two, provides enhanced diagnostic capabilities and efficacious treat-
ment modalities for veterans; and, three, supports the establish-
ment of policies and preventive measures that minimize the risk of
such illnesses during future military operations.

Dr. Feussner has addressed the role of the Research Working
Group, and therefore I shall now focus my comments on the DOD
program and the procedures we use to implement that program.

The Department of Defense uses competitive procedures to solicit
extramural proposals for scientific studies and research on Gulf
war veterans’ illnesses. This extramural research program is ad-
ministered for the DOD by the U.S. Army Medical Research and
Materiel Command at Fort Detrick. They possess unparalleled ex-
perience and have in place the contract clauses and review proc-
esses that are necessary for solicitation and selection of fully quali-
fied Proposals on merit factors of program relevance and scientific
excellence; for resolving complex and difficult issues of regulatory
compliance, such as the protection of human research subjects, en-
suring the welfare of research animals, the safe use of high-hazard
etiologic agents, research safety and surety for handling highly
toxic chemical warfare agent materials; and for rapid program
starts through application of streamlined extramural research ac-
quisition processes.

As was mentioned, these research proposals are solicited through
the use of either an open-ended broad agency announcement, BAA,
or through BAAs announcing specific research opportunities. These
announcements are formally made through publication in the Com-
merce Business Daily and may be accessed and downloaded from
the Internet.

Extramural research awards on Gulf war veterans’ illness may
result from an investigator responding to the openended BAA
which solicits medical and biomedical research ideas, with empha-
sis on those that are most relevant to ongoing medical research
programs. In order to do so, an investigator submits a preproposal,
usually 3 to 4 pages in length, which states the problem to be stud-
ied; the significance and/or uniqueness of the proposed effort; the
relevance to the defense biomedical and medical research pro-
grams; some relative cost information; an overview description of
any proposed use of animal or human subjects in the research; and


50

Mr. Towns. Dr. Barrett.

Ms. BARRETT. Thank you for the opportunity to review the De-
partment of Health and Human Services involvement in the coordi-
nated effort to address the health concerns of Gulf war veterans.

As you indicated, I am Dr. Drue Barrett. I am Chief of the Veter-
ans’ Health Activity Working Group of the National Center for En-
vironmental Health at the Centers for Disease Control and Preven-
tion. I serve as CDC’s liaison to the HHS on Gulf war issues, and
lam a member of the Research Working Group of the Persian Gulf
Veterans Coordinating Board.

Through its membership in the Research Working Group, HHS
has been involved in providing guidance and coordination for DOD,
VA, and HHS research activities relating to Gulf war veterans.
Specifically, this has included assessing the state and direction of
research, review of Government research concepts as they are de-
veloped, identification of gaps in factual knowledge and conceptual
understanding, and providing recommendations regarding research
direction.

When the input of experts on a specialized research topic is need-
ed, HHS scientists who are not regular members of the Research
Working Group have provided consultation and have participated
on special subcommittees managed by the Research Working
Group. Through participation on the Subcommittee for Project
Funding Recommendations, HHS has provided input into the pro-
grammatic review and funding recommendations of the Research
Working Group. The process that is involved is reviewed in my
written testimony.

HHS believes that the Research Working Group has developed
an appropriate and scientifically rigorous agenda for addressing the
health concerns of Gulf war veterans. This research agenda in-
cludes an important balance of clinical studies, epidemiologic inves-
tigations, and basic research.

Now I would like to briefly review CDC’s current research activi-
ties relating to Gulf war veterans and how these activities were se-
lected and funded.

In 1997, CDC developed a request for proposals which focused on
two programmatic priority areas: one, research that enhanced the
understanding of conditions and symptoms reported to be more
prevalent among Gulf war veterans; and two, research that added
to the scientific knowledge needed to develop a case definition of
illness among Gulf war veterans.

CDC convened a Special Emphasis Panel, known as SEP, com-
posed of 17 experts from outside CDC to review and rate the sci-
entific merit of the proposals received. In addition, a subcommittee
of the Research Working Group reviewed proposal abstracts and
SEP summary statements to determine the relevancy to the Fed-
eral research goals.

Based on the results of the SEP and the Research Working
Group reviews, two new studies were selected for funding. The Bos-
ton University School of Public Health will conduct a study exam-
ining “Cognitive Function and Symptom Patterns of Persian Gulf
Veterans.” Robert Wood Johnson Medical School will conduct a
study comparing various case definitions for unexplained illness


95

17

with directives from the Joint Chiefs of Staff, regarding
implementation of a standardized medical surveillance program.
The program expands capabilities in a number of areas including:
health education, risk communication, standardized medical
screening pre and post deployment, health hazards assessment, and
in-theater medical surveillance. Upon return from the
deployment, each service member will undergo health screening
with the results annotated on standardized forms for entry into a
central data base. In addition, DoD has established a
telemedicine network within Bosnia that allows the projection of
specialized diagnostic care and consultation forward to the
patient.

As an aside, DoD efforts to provide effective
countermeasures against medical risks in Bosnia include very
careful planning regarding the use of two INDs. Tickborne
Encephalitis (TBE) and Hemorrhagic Fever with Renal Syndrome
(HFRS) are two infectious diseases which present serious
potential health risks to U.S. forces operating in Bosnia. The
Department through the Army Surgeon General filed INDs to use
ribavirin as a treatment for HFRS and the Austrian TBE vaccine
for immunization of military personnel. Medical staff have been
notified that informed consent is required to administer these
pharmaceuticals. In both of these cases, DoD determination that
informed consent is feasible was based on a thorough analysis of
the nature and extent of the health risk presented, the treatment
context, the military situation, available alternatives, and,
most importantly, the best interests of the members.

CONCLUSION.

For the reasons stated above, the Department of Defense
urges that the petition be denied.


33

highlight important findings and initiatives resulting from the Federal GWVI program in 1997 and
identify some of the key avenues that the DoD, VA and DHHS are pursuing in 1998.
Importantly, we are trying to remain sufficiently flexible to be able to take advantage of new
findings and scientific leads.

Some groups of Gulf War veterans have an excess of self-reported symptoms in
‘comparison with non-deployed veterans. Although no connection has been made
between symptoms and specific disease pathology, ongoing and newly funded projects
are being directed at determining whether such a connection exists.

Published mortality studies through 1993 (and preliminary results through 1995) do not
demonstrate any excess of disease-specific deaths of Gulf War veterans when compared
to non-deployed veterans of the same era. The mortality rates of both veterans groups
are about half the rate of the general U.S. population. The Department will continue to
follow the mortality experience of veterans into the future.

A study of military hospitalizations indicated that, at least among active duty personnel,
the rate of hospitalizations of Gulf War veterans did not exceed that of their non-
deployed counterparts. This suggests that Gulf War veterans were not experiencing an
‘excess of illnesses of a severity that would lead to hospitalization.

One focused study of a small cohort of Gulf War veterans and a study of military
hospitalizations did not uncover an excess of birth defects among veterans’ offspring.
Another study examined the occurrence of Goldenhar Syndrome (a rare birth defect)
‘among the offspring of Gulf War veterans and, in those born to Gulf War era veterans in
military hospitals, found no statistically significant difference in the occurrence of
Goldenhar Syndrome.

There is some evidence that there are neuropsychological differences between veterans
reporting symptoms of GWVI and in a control population. Although the clinical
significance of these differences is unclear, research results suggest that the differences
may be due to psychological distress and exposure to neurotoxins. It has also been
shown that there is some attention and memory dysfunction in Gulf War veterans
diagnosed with posttraumatic stress disorder (PTSD). These areas of research continue
to be intensely pursued.

There is recent indication from follow-up studies of the Tokyo sarin poisoning that sarin
may have a subtle neurotoxic action that is unrelated to acute inhibitory action on brain
cholinesterase or to PTSD, which had been reported in these victims. The Department is,
placing increased emphasis on assessing long-term effects of exposure to chemical
warfare agents.

There is indication that stress can lead to an increase in the penetration of pyridostigmine

bromide across the blood-brain barrier, suggesting the possibility of central nervous
system effects. However, another study provides data that pyridostigmine bromide

10


168

CONCLUSIONS.

The ongoing epidemiological research cannot provide precise,
accurate, and conclusive answers regarding the causes of veterans’
illnesses because of researchers' methodological problems as well

as the following:

-- | Researchers have found it extremely difficult to gather
information about many key exposures. For example, medical
records of the use of pyridostigmine bromide tablets and
vaccinations to protect against chemical/biological warfare

exposures were inadequate.

Gulf War veterans were typically exposed to a wide array of
agents, making it difficult to isolate and characterize the
effects of individual agents or to study their combined

effects.

-- Most of the epidemiological studies on Gulf War veterans’
illnesses have relied only on self-reports for measuring most

of the agents to which veterans might have been exposed.

-- The information gathered from Gulf War veterans years after
the war may be inaccurate or biased. There is often no
straightforward way te test the validity of self-reported

exposure information, making it impossible to separate bias in

20


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7

comprehensive physical examination protocol. These examinations will be conducted at

18 VA medical centers nationwide and involve specialized examinations including

neurological, rheumatological, psychological, and pulmonary evaluations. Completion of

data collection is anticipated around mid-1999. When the National Survey is complete
we will have a much clearer picture of the prevalence of symptoms and illnesses among

Gulf War veterans.

‘The medical evaluations in Phase III are designed to determine whether or not:

1. Gulf War veterans have an increased prevalence of the following conditions frequently
reported in the literature compared to a control group of non-deployed veterans:
Chronic Fatigue Syndrome (CFS), Fibromyalgia (FM), neurologic abnormalities
including peripheral neuropathy and cognitive dysfunction, post-traumatic stress
disorder (PTSD), and measures of general health status.

2. The specific medical conditions of arthritis, dermatitis, hypertension, bronchitis, and
asthma that have been reported as more frequent among Gulf War veterans compared
to non-deployed veterans are of greater prevalence among deployed Gulf War veterans
upon objective clinical examination.

3. The prevalence of any of these conditions is greater among the spouses of Gulf War
veterans than among spouses of non~deployed veterans.

4, The prevalence of medical conditions and major birth defects found on a pediatric
physical examination in the children conceived after the war is greater for Gulf War
veterans than for non-deployed veterans.


61

screening results as true positive, true negative, false positive, or false negative. Three
hypotheses will be tested: (1) the rate of false positives of the Gulf War military personnel self-
reports of asthma are the same as the rate of false positives of the non-Gulf War military
personnel self-reports of asthma; (2) the self-report of asthma among Gulf War and non-Gulf
War military personnel is accurate and correlates with objective measures of asthma; and (3)
among the Gulf War military personnel, there is no association between exposures in the Gulf
War and the subsequent occurrence of asthma, Comparison of the false positive and false
negative rates for self-reported asthma between Gulf War and non-Gulf War military personnel
will allow us to estimate the degree of over-reporting of symptoms potentially attributable to
publicity associated with service in the Gulf War.

‘The University of lowa has also been funded by DoD to conduct validation studies of
additional health outcomes among participants of the telephone survey. These include validation
of depression, cognitive dysfunction, and multisystemic conditions. An interagency agreement is
currently being developed that will enable CDC investigators to provide technical assistance to
DoD and the University of Iowa for this study.

Finally, in response to House Report 105-205, HHS developed a research strategy for
addressing the health effects of exposure to multiple chemicals. The principal goal for FY°98 is
to develop a five-year research plan to investigate the relationship between possible biological
and chemical exposures in the Gulf War and subsequent illnesses among Gulf War veterans.
This will include joint sponsorship by CDC and the National Institute for Environmental Health
Sciences (NIEHS) of a consensus-building conference. The conference will strive to fully

characterize the nature of multiple chemical exposures within the Gulf War veteran population

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114

Mr. Chairman, I would yield back.

Mr. Suays. Thank you.

Mr. Sanders.

Mr. SANDERS. Thank you very much, Mr. Chairman. I am de-
lighted to see our guests here today.

What I would like to do, with your support, is just to wander a
little bit through the very fine report that this committee published
in November, which I thought is the outstanding—it is the best
piece of work I have seen in trying to understand the cause of—
or at least what has been going on with research and so forth.

As members of the committee may know, and let me quote from
the report, “This committee reluctantly concludes that responsibil-
ity for Gulf War illness, especially the research nda, must be
placed in a more responsive agency independent of the DOD and
the VA.” And I strongly agree with that conclusion.

This is not a personal criticism, but if I went to a physician for
6 years, and I said, Doctor, I am very, very sick, ma: I can’t go
to work, I have memory losses, I constantly am suffering from fa-
tigue, I have rashes, et cetera, and after 6 years that doctor told
me, I don’t understand what the cause of your problem is and I
have no treatment for you, I would say to that doctor, thank you
very much for your help, I am going elsewhere.

I think that’s probably the attitude of most members of the veter-
ans community and many Americans. And I think it is not good
enough to say it is a difficult problem. We recognize that it is a dif-
ficult problem. But I think today—and maybe in a moment you will
answer this question—if I were to say to you, where are we now
that we weren’t 6 or 7 years ago? it is the cause of Gulf war
illness? Don’t know. What treatments do you have? Don’t know.

And that’s not good enough, it seems to me. And I think we have
got to understand that.

No. 2, picking up on a point that Mr. Snowbarger made a mo-
ment ago, amazingly enough—and I would like you to address this
as well—there was a program—Mr. Chairman, you may have seen
it—Frontline, a couple of months ago, and Frontline on PBS is a
pretty good program, pretty respected. Their conclusion was basi-
cally—and I would like you to tell me whether you agree with it—
that there really is no Gulf war illness, that what we are suffering
from—that the problem is still stress and that this happens after
every war.

Nothing new here. It happened after the Civil War, World War
I, World War II. When people come home from the war, they are
sick, and there ain’t no cause for the problem.

I think when Mr. Snowbarger asked his question, basically the
thesis of that program, supported by former people in the VA, high-
ranking physicians, was there is no problem; that much of what
the chairman and I, Mr. Towns and others are trying to do is really
a waste of time and maybe we are opportunists, politicians, trying
to exacerbate fears among veterans and so forth. And maybe you
will comment on that.

But now I want to ask ve some—getting away from Washing-
ton, back home, let me tell you a few experiences I have had; and
I see everybody here is a physician, so maybe you can help me with
some answers.


116

of multiple chemical sensitivity, which seems to me an important
aspect of this whole discussion; people are overladen with chemi-
cals, who respond negatively.

What are we telling 70,000 vets about possible food—exposures
to chemicals that might be in their food? What should they stay
away from?

Furthermore, after 7 years, what kind of treatment protocols
have you developed? If I am a Persian Gulf vet and I have memory
loss, I have—one guy was telling me he sleeps 14 hours a night and
still doesn’t feel refreshed. What treatment do we have? After 7
years, is there any treatment?

Now, second of all, with regard to that, there are some people in
the outside world who are trying to develop treatments. We have
heard from a few physicians here. There were some physicians in
the VA who did not seem to be able to stay in the VA for a very
long time.

We heard from Dr. Nicholson, who has an idea. Is he right? I
don’t know if he is right, but how are we responding to his
thoughts, to other people’s thoughts?

So I would like you maybe to respond to some of those concerns.
And I have gone on too long and thank you, Mr. Chairman.

Mr. SHays. No, you haven’t gone on too long, and maybe, just to
followup to make sure the different parts are answered, we have
simply for all of you—if you can’t remember all of his questions,
but I would like you to try to go down them so we will use the time
to do that.

Mr. SANDERS. Thank you, Mr. Chairman.

Mr. Suays. Except the part about whether people are being op-
portunistic, we will leave that out.

Dr. FEUSSNER. Well, I would say that it is not my perception that
you are opportunistic.

You asked a lot of questions, and I tried to track them. I will go
down the list and do the best I can.

Mr. SANDERS. Thank you.

Dr. FEUSSNER. The first issue you have asked me before, regard-
ing turning the research effort over to an independent agency, and
I think you know that my own perspective is different from yours.
I view our research program as vigorous. I believe that we have

otten inputs from the best scientists in the United States. I be-
lieve that we have solicited inputs and have funded scientists from
the international community as well.

It is a broad research effort, and so it can be viewed as diffuse,
but I don’t think so. I think we are trying to cover all the reason-
able bases.

We have made critical observations, yes, and this committee has
heard those before—about mortality, about hospital use, about
birth defects. You have not heard any definitive information about
what the cause of this is; and that is correct, I do not know what
the cause is.

As I said earlier, I don’t know what the cause of hypertension is
in most of my patients, but I have very effective treatment for that
illness; and I take your point on that as well, and we will get to

t.


4

I am in awe of all of you for that. But if you would stand, I will
swear you all in.

[Witnesses sworn.]

Mr. Suays. For the record, all of the witnesses have responded
in the affirmative.

If we could go in the way I called you, Dr. Feussner, you are first
and we look forward to your testimony. What I am going to do is,
I am going to have a clock on and it will be on for 5 minutes, and
then I will click it on for another 5, and if you could kind of finish
up in that second 5, that would be great. So good to have you.

STATEMENTS OF JOHN FEUSSNER, M.D., CHIEF RESEARCH
AND DEVELOPMENT OFFICER, DEPARTMENT OF VETERANS
AFFAIRS, ACCOMPANIED BY TIMOTHY GERRITY, SPECIAL
ASSISTANT TO THE CHIEF RESEARCH AND DEVELOPMENT
OFFICER; ANNA JOHNSON-WINEGAR, DIRECTOR, ENVIRON-
MENTAL AND LIFE SCIENCES, DEPARTMENT OF DEFENSE;
DRUE H. BARRETT, PH.D., DIVISION OF ENVIRONMENTAL
HAZARDS AND HEALTH EFFECTS, NATIONAL CENTER FOR
ENVIRONMENTAL HEALTH, CENTERS FOR DISEASE CON.
TROL AND PREVENTION, U.S. PUBLIC HEALTH SERVICE;
AND SHEILA NEWTON, NATIONAL INSTITUTE OF ENVIRON-
MENTAL HEALTH SCIENCES, DEPARTMENT OF HEALTH AND
HUMAN SERVICES

Dr. FEUSSNER. Good morning, Mr. Chairman, other members of
the committee. Thank you for this opportunity to discuss the status
of the Federal research program on Gulf war veterans’ illness.

As you indicated, I serve as the Department of Veterans Affairs’
Chief Research and Development Officer and chairperson of the Re-
search Working Group of the Persian Gulf Veterans Coordinating
Board. The primary charge to the Research Working Group is to
assess the state and direction of research, identify potential new
approaches, collect and disseminate scientifically peer-reviewed re-
search information, and ensure that appropriate peer review and
oversight are applied to research conducted and sponsored by us,
the Federal Government.

The Research Working Group has guided the Federal research
portfolio using a number of different sources of input. These
sources include results from ongoing research; various expert pan-
els and oversight committees, such as the Institute of Medicine, the
Defense Science Board, the National Institutes of Health; several
congressional committees, including this co: ssional committee;
the Presidential Advisory Committee on Gulf War Veterans’ IIl-
nesses; independent scientists; and veterans. The Research Work-
ing Group, has synthesized this advice and information into a re-
search strategy embodied in a working plan for research on Persian
Gulf veterans’ illness.

This morning I want to highlight three of the ongoing research
efforts into Gulf war veterans’ illness.

Shortly after the June 1996 announcement of events at
Khamisiyah, the Research Working Group met and acted to rec-
ommend funding by DOD of three proposals that had previous
been deemed scientifically meritorious. The three projects are val.
ued at approximately $2.5 million and involve investigations con-



93

15

used safely for more than 40 years as the principle treatment for
myasthenia gravis at much higher doses over much longer periods
than the regimen used in the Gulf. The drug does have side
effects, but these are relatively mild. The evidence does not
suggest a difference in safety between use by men and women. The
recently published studies conducted by Moss and by Abou-Donia in
cockroaches and chickens, respectively, used extraordinarily high
dosages and routes of administration that differed from the route
of administration used by Service members in the Gulf. Although
providing potentially valuable preliminary scientific
information, these data cannot be generalized to a human
population. Similarly, decades of experience with botulinum
toxoid vaccine provide a clear basis for confidence concerning
safe use. The overwhelming weight of evidence continues to
support the safety of these two IND products.

The efficacy of pyridostigmine has been questioned based on
an Army study suggesting that it decreases the effectiveness of
atropine and pralidoxime chloride against nerve agents sarin and
VX. Pyridostigmine is used to counter soman poisoning based on
evidence that it substantially enhances the effectiveness of the
post exposure treatments against soman. Although it does
decrease somewhat the effectiveness of atropine and pralidoxime
against sarin and VX, the two treatments are so highly effective
against sarin and VX, that any negative interaction of
pyridostigmine and the nerve agent would be overwhelmed by the
atropine/pralidoxime therapy. Thus, in predicted clinical
outcome, pyridostigmine substantially improves medical protection
against soman and does not affect medical protection against
sarin and VX. In preparing medical countermeasures against the
possibility of chemical weapons attack using any of these nerve
agents, as was necessary in the Gulf War, predicted clinical
outcome clearly calls for the use of pyridostigmine.’

7 The results of the sarin/VX study were reported to the FDA
by the Army component responsible for administration of the
pyridostigmine IND in full compliance with 21 CFR § 312.33. The
study, conducted under a different Army command element, was
unknown to the IND investigators until it was published. In any
event, the results of the study do not affect the DoD or FDA
conclusions regarding the evidence of efficacy of pyridostigmine
for this clinical purpose.


38

3. Safety and Occupational Health Programs for Specific Research Areas:

a. Recombinant DNA. Research involving recombinant DNA must meet or exceed NIH
Guidelines for Research Involving Recombinant DNA Molecules, latest edition. The
proposal should discuss these requirements, as appropriate. The PI must have written
approval from the organizational Institutional Biosafety Committee prior to the proposed
DNA work.

b. Chemical Surety Materiel (neat and dilute) and Chemical Warfare Agent Analogs. A.
facility safety and security plan (FSSP) is required for all facilities using chemical agents
for research. Initial and recurring inspections by government safety personnel are required.
A Chemical Warfare (CW) agent analog is a compound which structurally resembles that
of a CW agent and exhibits similar chemical properties and pathophysiological effects.

Use of CW agent analogs will not be used in USAMRMC sponsored medical chemical
defense research except by special approval in rare instances, Full justification, including
special safety provisions, is required for the proposed use of CW agent analogs

. Infectious Disease Safety Program. Research involving biological or infectious disease
agents must demonstrate compliance with CDC/NIH Guidelines and OSHA regulations
for universal precautions and safety in blood-borne pathogens.

d, Medical Biological Defense Research Safety Program. Research performed for
biological defense must meet requirements of 32 CFR 626 and 627 and USAMRMC
policy. Provide the following information:

(1) List of the etiologic agents (including microorganisms, toxins, toxoids, etc.) to be
used in the proposed research.

(2) Recommended biosafety level appropriate for safe conduct and biocontainment.

(B) Describe special laboratory features and/or procedures that ensure personnel and
environmental safety.

(4) Describe the organizational biological safety program, including safety committee
reviews, inspections, and standing operating procedures for the safe use, handling,
transportation, storage, and disposal of potentially hazardous biological materials.

(5) Formal agreements documenting coordination with local (community outside the
organization) emergency authorities (including fire, health, and police officials) are
required for research funded by the Biological Defense Research Program (BDRP).
The documentation from the organization must include information such as potential
hazards that may be encountered, symptoms of exposure, recommended treatment of
exposure, and personal protective equipment required for responders. The formal
agreement must be signed by each community official (fire, health, and police) official.

22


158

when DOD acknowledged potential exposures to chemical agents at
Khamisiyah, Iraq. The failure to fund such research cannot be
traced to an absence of investigator-initiated submissions.
According to DOD officials, three recently funded proposals on low-

level chemical exposure had previously been rejected.”

PRIVATE SECTOR PURSUED VARIETY OF HYPOTHESES

A substantial body of research suggests that low-level exposures to
chemical warfare agents or chemically related compounds, such as
certain pesticides, are associated with delayed or long-term health
effects. For example, abundant evidence from animal experiments,
studies of accidental human exposures, and epidemiologic studies of
humans shows that low-level exposures to certain organophosphorus
compounds, including sarin nerve agents to which our troops may
have been exposed, can cause delayed, chronic neurotoxic effects.
‘This syndrome is characterized by clinical signs and symptoms
manifested 4 to 21 days after exposure to organophosphate
compounds. The symptoms of delayed neurotoxicity can take at least
two forms: (1) a single large dose may cause nerve damage with
paralysis and later spastic movement, and (2) repetitive low doses

may damage the brain, causing impaired concentration and memory,

“The three previously unfunded proposals address central nervous
system targets for organophosphates, development of a DNA-based
method for assessing exposures to mustard agent, and work on the
pharmacokinetics of the nerve agent VX.

10


125

going to do research on the Gulf war illness of whatever kind,
whatever seems interesting, strikes me as not having enough of a
focus on what exactly it is we are trying to look at.

I can envision, for as long as people who served in the Gulf are
alive, there are research proposals that could be undertaken. And
I am wondering whether there is enough policy guidance in terms
of what—you know, what you are looking for, to be productive.

Dr. FEUSSNER. You would like the policy guidance to be specific
enough so the research projects are focused within the area of in-
terest, but not so specific enough that they exclude research
projects that might be relevant.

And I think one of the reasons that we ask the several constitu-
ent members of the Research Working Group to have these docu-
ments reviewed before they are released is an effort to get enough
input to try to walk the line between being sufficiently specific
without being overly prescriptive. On the one hand, the danger
being that you are not focused enough; on the other hand, the dan-
ger is that you are being overly exclusive. And we do try to walk
that line to give sufficient guidance so that the investigators know
what to submit or know that this is an area of high priority and
their research fits into that area, without being prescriptive.

Mr. ALLEN. One last area of questions.

How much—you mentioned earlier, and I thought it was an in-
teresting suggestion, that—you know, if you had treatments for
multiple chemical sensitivity, you might not need to know the cau-
sation. Is that followed up in any of the research you are doing?
I mean, are you working on research that was more focused on the
treatment than on the causation?

Dr. FEUSSNER. Well, I think Mr. Sanders’ criticism on that is fair
criticism. At the moment. We have no active treatment trials ongo-
ing in any of these areas. We are trying to stimulate treatment
trials initially in chronic fatigue syndrome and fibromyalgia. We
have had discussions about antibiotic treatment protocols, not with
Dr. Nicholson but with the folks at Walter Reed, who also have ex-
pertise in mycoplasma problems.

And we specifically released a program announcement that is
open-ended and solicits research on any treatment modality with
tl requirements: No. 1, that the patient population who would
be the subject of the experiment are clearly defined; No. 2, that the
treatment protocols are replicable so if we show this treatment
works we can just disseminate it throughout the country; and No.
8, that the outcome measures, if not precise, at least use valid in-
struments to make the measures. Those were the only three cave-
ats.

Now, it is an open-ended program announcement. There are no
deadlines.

Mr. ALLEN. It seems to me a very important area to pursue.

With that, Mr. Chairman, I would yield back.

Mr. SHays. Thank you. The Chair recognizes Mr. Kucinich for 5
minutes and then another 5 minutes for 10.

Mr. KucinicuH. Thank you very much, Mr. Chairman. The ques-
tion to Dr——

Dr. FEUSSNER. Feussner.

Mr. KucINIcH [continuing]. Feussner?


100

that their individual interests aye subordinated to ‘those of the
mission and their unit. ‘Thus, although it would be in
servicepersons' individual best interests to not fight when they
are ill, as from malaria or dysentery, commanders may send them to
the front, regardless of their illness, if this is necessary to
benefit the mission or other servicepersons. Similarly, if an
individual serviceperson did not want to carry a canteen, wear
protective clothing, or be vaccinated against an endemic disease,
the commander could not permit this serviceperson to exercise

autonomy in this manner since this would unnecessarily endanger the

serviceperson and, consequently, the mission and other
servicepersons in the unit.

Servicepersons are aware that as they approach actual
fighting, their autonomy dramatically may decrease. They
understand that their commander may order them to enter life-
threatening situations under enemy fire, and make any number of
other decisions to benefit the mission or the unit. These may
include their commanders requiring them to make use of protective
devices during combat.

As I already have stated, when servicepersons join the
military, they agree to subordinate their own interests and
autonomy to the military when necessary for the mission or their
unit. This promise is also reciprocated, however, by the military.
The military, in turn, promises all servicepersons that it will
protect their lives during combat to the maximal degree that this
is possible, contingent, of course, on its fulfilling the needs of

the mission.


41

> Itis DA policy that the contractor must make provision for all necessary medical care of
research subjects for injury or disease which is the proximate result of participation in the
research.

c. Department of Defense Directive 6465.2, dated 19 April 1984, stipulates that organs,
tissues, or tissue fluids obtained from an autopsy shall not be used for research or
investigational purposes without the expressed consent of the next of kin. It should be noted
that a general autopsy consent may not, in itself, be sufficient. If autopsy tissue is to be used,
the protocol should include a copy of the consent form used to obtain the tissue. All studies
involving the use of anatomical substances must include a completed Optional Form 310 and
documentation of Institutional Review Board review and approval to conduct the study. This
documentation must include the level of risk assigned to the study. If the Institutional
Review Board determines the study to be exempt from human use regulations, a letter signed
by the Institutional Review Board Chairperson must be included stating the study is exempt.

d. It is the policy of the USAMRMC that organs, tissues, or tissue fluids obtained from a
surgical procedure shall not be used for research or investigational purposes without the
expressed consent of the patient or the patient's legal representative. It should be noted that
a consent to perform surgery may not, in itself, be sufficient. If excised tissue is to be used,
the protocol should include a copy of the consent form used to obtain the tissue. All studies
involving the use of anatomical substances must include a completed Optional Form 310 and
documentation of Institutional Review Board review and approval to conduct the study. This
documentation must include the level of risk assigned to the study. If the Institutional
Review Board determines the study to be exempt from human use regulations, a letter signed
by the Institutional Review Board Chairperson must be included stating the study is exempt.

¢. It is the policy of the USAMRMC that any anatomical substance (organs, tissues, or tissue
fluids) linked by identifiers to a particular person and used for research under a USAMRMC
sponsored contract shall be donated for the purpose of research or investigation. The donor
shall be the person from whom the substance is removed or, in the event of death or legal
disability of the person from whom the substance is removed, the next of kin or legal
representative of such person, Donation shall be made by written consent and the donor shall
relinquish all ownership and/or rights to the substance. All human anatomical substances
used in research under contract shall be lawfully acquired. It should be noted that a general
autopsy consent form or a consent to perform surgery in and of themselves, may not be
adequate. If excised or autopsy tissue is to be used, the protocol should include a copy of the
consent form used to obtain the tissue. All studies involving the use of anatomical substances
must include a completed Optional Form 310 and documentation of Institutional Review
Board review and approval to conduct the study. This documentation must include the level
of risk assigned to the study. If the Institutional Review Board determines the study to be
exempt from human use regulations, a letter signed by the Institutional Review Board
Chairperson must be included stating the study is exempt.

£. Prisoners of War shall not be used as research subjects.

32