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[House Hearing, 106 Congress]
[From the U.S. Government Publishing Office]

     FORCE PROTECTION: IMPROVING SAFEGUARDS FOR ADMINISTRATION OF 
        INVESTIGATIONAL NEW DRUGS TO MEMBERS OF THE ARMED FORCES

=======================================================================

                                HEARING

                               before the

                   SUBCOMMITTEE ON NATIONAL SECURITY,
                  VETERANS AFFAIRS, AND INTERNATIONAL
                               RELATIONS

                                 of the

                              COMMITTEE ON
                           GOVERNMENT REFORM

                        HOUSE OF REPRESENTATIVES

                       ONE HUNDRED SIXTH CONGRESS

                             FIRST SESSION

                               __________

                            NOVEMBER 9, 1999

                               __________

                           Serial No. 106-123

                               __________

       Printed for the use of the Committee on Government Reform

  Available via the World Wide Web: http://www.gpo.gov/congress/house
                      http://www.house.gov/reform

                                 ______

                     U.S. GOVERNMENT PRINTING OFFICE
64-776 CC                    WASHINGTON : 2000

                     COMMITTEE ON GOVERNMENT REFORM

                     DAN BURTON, Indiana, Chairman
BENJAMIN A. GILMAN, New York         HENRY A. WAXMAN, California
CONSTANCE A. MORELLA, Maryland       TOM LANTOS, California
CHRISTOPHER SHAYS, Connecticut       ROBERT E. WISE, Jr., West Virginia
ILEANA ROS-LEHTINEN, Florida         MAJOR R. OWENS, New York
JOHN M. McHUGH, New York             EDOLPHUS TOWNS, New York
STEPHEN HORN, California             PAUL E. KANJORSKI, Pennsylvania
JOHN L. MICA, Florida                PATSY T. MINK, Hawaii
THOMAS M. DAVIS, Virginia            CAROLYN B. MALONEY, New York
DAVID M. McINTOSH, Indiana           ELEANOR HOLMES NORTON, Washington, 
MARK E. SOUDER, Indiana                  DC
JOE SCARBOROUGH, Florida             CHAKA FATTAH, Pennsylvania
STEVEN C. LaTOURETTE, Ohio           ELIJAH E. CUMMINGS, Maryland
MARSHALL ``MARK'' SANFORD, South     DENNIS J. KUCINICH, Ohio
    Carolina                         ROD R. BLAGOJEVICH, Illinois
BOB BARR, Georgia                    DANNY K. DAVIS, Illinois
DAN MILLER, Florida                  JOHN F. TIERNEY, Massachusetts
ASA HUTCHINSON, Arkansas             JIM TURNER, Texas
LEE TERRY, Nebraska                  THOMAS H. ALLEN, Maine
JUDY BIGGERT, Illinois               HAROLD E. FORD, Jr., Tennessee
GREG WALDEN, Oregon                  JANICE D. SCHAKOWSKY, Illinois
DOUG OSE, California                             ------
PAUL RYAN, Wisconsin                 BERNARD SANDERS, Vermont 
HELEN CHENOWETH-HAGE, Idaho              (Independent)
DAVID VITTER, Louisiana

                      Kevin Binger, Staff Director
                 Daniel R. Moll, Deputy Staff Director
           David A. Kass, Deputy Counsel and Parliamentarian
                      Carla J. Martin, Chief Clerk
                 Phil Schiliro, Minority Staff Director
                                 ------                                

Subcommittee on National Security, Veterans Affairs, and International 
                               Relations

                CHRISTOPHER SHAYS, Connecticut, Chairman
MARK E. SOUDER, Indiana              ROD R. BLAGOJEVICH, Illinois
ILEANA ROS-LEHTINEN, Florida         TOM LANTOS, California
JOHN M. McHUGH, New York             ROBERT E. WISE, Jr., West Virginia
JOHN L. MICA, Florida                JOHN F. TIERNEY, Massachusetts
DAVID M. McINTOSH, Indiana           THOMAS H. ALLEN, Maine
MARSHALL ``MARK'' SANFORD, South     EDOLPHUS TOWNS, New York
    Carolina                         BERNARD SANDERS, Vermont 
LEE TERRY, Nebraska                      (Independent)
JUDY BIGGERT, Illinois               JANICE D. SCHAKOWSKY, Illinois
HELEN CHENOWETH-HAGE, Idaho

                               Ex Officio

DAN BURTON, Indiana                  HENRY A. WAXMAN, California
            Lawrence J. Halloran, Staff Director and Counsel
                Robert Newman, Professional Staff Member
                Marcia Sayer, Professional Staff Member
                         Jason M. Chung, Clerk
           David Rapallo, Minority Professional Staff Member
                            C O N T E N T S

                              ----------                              
                                                                   Page
Hearing held on November 9, 1999.................................     1
Statement of:
    Caplan, Arthur, Ph.D., director, Center for Bioethics, 
      University of Pennsylvania; and Charles McCarthy, Ph.D., 
      senior research fellow, Kennedy Institute of Ethics, 
      Georgetown University......................................    59
    Spotila, John, Administrator, Office of Information and 
      Regulatory Affairs, Office of Management and Budget; Sue 
      Bailey, Assistant Secretary of Defense for Health Affairs, 
      Department of Defense; and William Raub, Deputy Assistant 
      Secretary, Science Policy, Health and Human Services.......     4
Letters, statements, et cetera, submitted for the record by:
    Bailey, Sue, Assistant Secretary of Defense for Health 
      Affairs, Department of Defense, prepared statement of......    13
    Caplan, Arthur, Ph.D., director, Center for Bioethics, 
      University of Pennsylvania, prepared statement of..........    61
    McCarthy, Charles, Ph.D., senior research fellow, Kennedy 
      Institute of Ethics, Georgetown University, prepared 
      statement of...............................................    75
    Raub, William, Deputy Assistant Secretary, Science Policy, 
      Health and Human Services, prepared statement of...........    24
    Shays, Hon. Christopher, a Representative in Congress from 
      the State of Connecticut, prepared statement of............     3
    Spotila, John, Administrator, Office of Information and 
      Regulatory Affairs, Office of Management and Budget, 
      prepared statement of......................................     7

 
     FORCE PROTECTION: IMPROVING SAFEGUARDS FOR ADMINISTRATION OF 
        INVESTIGATIONAL NEW DRUGS TO MEMBERS OF THE ARMED FORCES

                              ----------                              

                       TUESDAY, NOVEMBER 9, 1999

                  House of Representatives,
       Subcommittee on National Security, Veterans 
              Affairs, and International Relations,
                            Committee on Government Reform,
                                                    Washington, DC.
    The subcommittee met, pursuant to notice, at 10:10 a.m., in 
room 2154, Rayburn House Office Building, Hon. Christopher 
Shays (chairman of the subcommittee) presiding.
    Present: Representatives Shays, Towns, Allen, and Sanders.
    Staff present: Lawrence J. Halloran, staff director and 
counsel; Robert Newman and Marcia Sayer, professional staff 
member; Jason M. Chung, clerk; David Rapallo, minority 
professional staff member; and Earley Green, minority staff 
assistant.
    Mr. Shays. Good morning. I would like to call this hearing 
to order.
    Under what circumstances should U.S. military personnel be 
given investigational drugs or vaccines without their consent?
    The answer involves complex and controversial issues of 
medical ethics and military doctrine. Under Federal regulations 
known as the ``Common Rule,'' every person asked to use an 
investigational medical product must be informed of the 
expected benefits and risks, and they must give their consent.
    Prior to the Gulf war, there had been no sanctioned 
military exception to those longstanding, important informed 
consent requirements. But the threat of chemical and biological 
warfare continues to force military doctors to look for new 
drugs and vaccines to treat or protect against exposure to 
unconventional weapons.
    Because those medicines cannot be tested for efficacy 
without unethical risk to human subjects, they are considered 
investigational. Because the Department of Defense [DOD], 
considers use of investigational drugs essential treatment, not 
research, they see the need for waivers of informed consent 
requirements in deference to the demands of the battlefield.
    A balance between military necessity and individual dignity 
is not easily struck. Experience in the Gulf war and in Bosnia 
remains instructive both as to the needs for waivers and the 
need for more rigorous standards to guide their formulation and 
execution. After extensive hearings on DOD's failure to provide 
basic information or maintain individual medical records for 
investigational products used in the Persian Gulf, we 
recommended legislation to require the President's approval for 
all future waivers.
    Last year's Defense Authorization Act contained provisions 
reflecting our recommendations.
    Today, we examine the President's Executive order and the 
Food and Drug Administration [FDA], regulation implementing 
that law.
    New procedures and safeguards should address many of the 
weaknesses of the previous waiver rules. Scientific standards 
have been strengthened and made more explicit. Independent, 
nongovernment members have been added to the Institutional 
Review Board charged to approve and monitor waiver protocols. 
Subject only to security constraints, notice of waiver 
decisions must be published.
    But protections on paper are not enough. We seek assurances 
from DOD that essential protections, particularly medical 
recordkeeping, will not be left behind again when mandatory 
drugs and vaccines are shipped to the battlefield. And we need 
to know the Department of Health and Human Services [HHS], will 
be vigilant in enforcing waiver conditions to protect the 
health and the rights of military personnel.
    Our witnesses this morning bring a great depth of knowledge 
and many years of experience to these important questions, and 
we look forward very much to their testimony.
    At this time, having not given the gentleman time to relax 
here, but we welcome you here and welcome any opening statement 
you would like to make.
    OK. Thank you.
    Well, if I could, let me just deal with our requirements to 
ask unanimous consent that all members of the subcommittee be 
permitted to place an opening statement in the record and that 
the record remain open for 3 days for that purpose. Without 
objection, so ordered.
    And I ask further unanimous consent that all Members be 
permitted to include their written statement in the record. 
Without objection, so ordered. And to inform our witnesses that 
their statements clearly will be part of the record and would 
welcome them making any point they want that may be even in 
addition to their statement for the record.
    [The prepared statement of Hon. Christopher Shays follows:]
    [GRAPHIC] [TIFF OMITTED] T4776.001
    
    Mr. Shays. At this time, we have three witnesses: John 
Spotila, Administrator, Office of Information and Regulatory 
Affairs, Office of Management and Budget, and he'll speak 
first. Then we have Dr. Sue Bailey, Assistant Secretary of 
Defense for Health Affairs, Department of Defense. And then we 
have William Raub, Dr. William Raub, Deputy Assistant Secretary 
of Science Policy, Department of Health and Human Services.
    So we have three excellent witnesses that will be able to 
help us sort this issue out, and I would invite them to stand 
so we could administer the oath which we do in this committee 
to all witnesses who testify.
    [Witnesses sworn.]
    Mr. Shays. Thank you. Note for the record that all three 
witnesses responded in the affirmative to the oath, and we'll 
start with OMB.
    What we do with our clock is we turn it on for 5 minutes. 
You're allowed to go over, but we want you to be as close to 5 
as you want; and, after 10, the gavel goes down hard. 
Hopefully, we don't get to 10.

     STATEMENTS OF JOHN SPOTILA, ADMINISTRATOR, OFFICE OF 
 INFORMATION AND REGULATORY AFFAIRS, OFFICE OF MANAGEMENT AND 
 BUDGET; SUE BAILEY, ASSISTANT SECRETARY OF DEFENSE FOR HEALTH 
   AFFAIRS, DEPARTMENT OF DEFENSE; AND WILLIAM RAUB, DEPUTY 
 ASSISTANT SECRETARY, SCIENCE POLICY, HEALTH AND HUMAN SERVICES

    Mr. Spotila. Good morning, Chairman Shays and members of 
the subcommittee. Thank you for inviting me here today to 
discuss Executive Order 13139 which represents a thoughtful 
effort to implement the Strom Thurmond National Defense 
Authorization Act for fiscal year 1999. We appreciate your 
strong, continuing interest in protecting the health of our 
military personnel.
    Before discussing the order in detail, let me summarize the 
events leading to its issuance.
    Prior to the Persian Gulf war, the Department of Defense 
concluded that Iraq had chemical and biological agents that 
posed great risk for our deploying troops. DOD identified 
specific drugs that could counter the effects of these agents, 
but the drugs were not yet approved by the FDA for that 
specific use.
    For the Gulf war, FDA granted DOD waivers of the need to 
obtain informed consent for the use of two such drugs, PB, 
potentially useful against nerve gases, and bot tox, a vaccine 
against botulism. My understanding is that DOD only implemented 
the waiver for PB.
    In evaluating the use of this waiver during the Gulf war, 
we learned many lessons. In 1997, FDA sought public comment on 
whether its rule permitting military waivers of informed 
consent should be revoked or revised. FDA submitted a revised 
rule to OMB on this subject in June 1998, leading the 
administration to initiate an interagency process to develop a 
coordinated policy on this issue.
    Meanwhile, Congress acted to ensure that DOD would have a 
modified mechanism to request waivers of informed consent. 
Section 1107 of the 1999 Defense Authorization Act gave to the 
President authority to grant waivers of informed consent upon a 
request from the Secretary of Defense if the President finds 
that obtaining informed consent is not feasible or is contrary 
to the best interest of the military member or is not in the 
interests of national security.
    To implement this act and after reviewing the results of 
the interagency process coordinated by OMB, the President 
signed Executive Order 13139. The order establishes new 
procedures for the consideration of a DOD waiver request and is 
supplemented by a companion FDA rule establishing the standards 
and criteria that the President will apply in making the waiver 
determination.
    The President has decided to apply these standards and 
criteria, even in the national security area, as further 
protection for our troops.
    Both the order and the rule reflect a consensus reached by 
all of the relevant agencies on the best means of implementing 
the act.
    Our policy continues to be that the U.S. Government 
normally will only administer products approved for their 
intended use by FDA. In what we hope will be very limited 
circumstances, however, protection of our deployed military 
personnel may require use of an investigational drug. Even in 
most of those situations, DOD would administer such products 
with the consent of the individual military member.
    Under certain rare circumstances, however, and with strict 
controls, it may need to administer such products without 
obtaining an individual's consent in order to preserve military 
capability in a particular operation and to protect the health 
and well-being of our deployed troops. It is only under these 
limited circumstances that DOD would seek a waiver, and the 
President would grant it only when necessary.
    The order establishes a process for waiver decisions to be 
carefully evaluated in a timely manner and used only when 
absolutely necessary, creates multiple layers of oversight to 
ensure accountability and proper safeguards for military troops 
and builds in additional procedures and safeguards to protect 
the health and well-being of our military troops prior to, 
during and after a particular military operation.
    When the Secretary of Defense makes a waiver request, it 
must contain a full description of the threat, written 
documentation that the Secretary has complied with each of 
FDA's standards and criteria and additional pertinent 
information. To ensure that FDA is brought into the 
decisionmaking process early, the Secretary must develop the 
waiver request in consultation with FDA. Before a waiver 
request can be made, an Institutional Review Board must review 
DOD's protocols for military use of investigational drugs.
    The FDA Commissioner must certify to the President's 
national security and science advisers whether FDA's standards 
and criteria have been adequately addressed and whether the 
investigational new drug protocol should proceed. The 
Commissioner will base this certification on a complete 
assessment of the criteria specified in the rule, including 
FDA's own analysis of the safety and effectiveness of the 
investigational drug in relation to the medical risk that could 
be encountered.
    The President's national security and science advisers then 
carefully review the submission and prepare a joint advisory 
opinion for the President, recommending whether the waiver of 
informed consent should be granted. The President then will 
approve or deny the waiver request.
    If a waiver request is granted, the DOD offices 
implementing the waiver, DOD's Inspector General and the FDA 
all conduct review and monitoring to assess whether DOD 
continues to meet the standards and criteria. DOD must report 
any changed circumstances to the President and must comply with 
any additional reporting requirements that the President 
specifies at the time of approval.
    To increase public accountability, the act also requires 
the Secretary to notify the congressional defense committees 
and the public that a waiver has been granted.
    As further protection for our troops, the order requires 
DOD to provide training and health risk communication on the 
requirements of using an investigational drug in support of a 
military operation to all military personnel, including those 
in leadership positions. In the event that DOD requests a 
waiver, DOD must submit its training and health risk 
communication plans to FDA and the reviewing IRB.
    These steps seek to ensure that all military personnel 
required to take the investigational drug are fully informed.
    Finally, the order places a time limit on the waiver. It 
will expire at the end of 1 year or less as specified by the 
President. If the Secretary seeks to renew a waiver prior to 
its expiration, the Secretary must submit to the President an 
updated request and must satisfy all of the criteria for a 
waiver. The President may also revoke the waiver based on 
changed circumstances or for any other reason at any time.
    The order seeks to minimize the need for waivers. It 
directs DOD to collect intelligence in advance on potential 
health threats that may be encountered in an area of operation 
and to work with HHS to ensure that appropriate counter 
measures are developed. DOD will study these potential products 
to determine whether each is safe and effective for its 
intended use.
    Both Departments have committed to a collaborative effort 
to speed up the drug approval process, further minimizing the 
need for such a waiver in the future. These are all positive 
steps for protecting the health of our military personnel.
    We hope that DOD will not need to invoke the waiver 
procedure at all in the future. If it does find it necessary, 
however, the order, combined with FDA's new interim final rule, 
will significantly improve the safeguards necessary to protect 
the health of our military personnel.
    Thank you for the opportunity to discuss the 
administration's efforts in this area. I would be pleased to 
answer any questions you may have.
    Mr. Shays. Thank you.
    [The prepared statement of Mr. Spotila follows:]
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    Mr. Shays. Dr. Bailey.
    Dr. Bailey. Congressman Shays, members of the committee, I 
am happy to be here today to discuss the Executive order.
    You know, we are obligated to provide the best protection 
we are capable of in providing our troops protection against 
chemical and biological warfare. The United States today faces 
the monumental challenge of establishing quickly a credible 
medical defense against these weapons. Unfortunately, for most 
chemical and biological agents such as soman, plague, 
tourilinea, botulinum and other toxins and bioengineered 
substances there are not yet available, effective FDA-approved 
prevention or treatment products.
    Research, development and production of such products will 
take, in fact, many years, even with FDA's commendable new 
animal efficacy rules.
    The Department is committed to moving IND products to 
licensure as quickly and efficiently as possible. In the 
meantime, however, the best medical judgments available will 
demand the use of some products classified by the FDA as 
investigational. When an investigational product is the only 
means available to protect against a lethal chemical or 
biological weapon, the lives of individual members, the safety 
of their comrades who rely on them and the success of the 
military mission require a uniform use of that medical 
protection.
    DOD believes that the President must be given a range of 
options, including the feasible use of these investigational 
products for providing credible medical protection against 
chemical biological weapons. The Executive order provides the 
President with that framework and the flexibility, when 
essential, to waive informed consent. DOD will be working 
closely, interagency with FDA, to develop the appropriate 
protocol and procedures to enforce this new Executive order.
    Thank you.
    Mr. Shays. Thank you.
    [The prepared statement of Ms. Bailey follows:]
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    Mr. Shays. Dr. Raub.
    Mr. Raub. Mr. Chairman, with your permission, I will make a 
short statement now and ask that my long statement be submitted 
to the record.
    Mr. Shays. That's fine.
    Mr. Raub. Good morning, Mr. Chairman, Mr. Sanders. I am 
William F. Raub, Deputy Assistant Secretary for Science Policy 
at the Department of Health and Human Services.
    I appreciate this opportunity to discuss policies governing 
the administration of investigational medical products to U.S. 
military personnel, in particular the safeguards included in 
President Clinton's Executive Order 13139 and the new Food and 
Drug Administration interim rule on waiver of informed consent.
    Protection of individuals receiving health care services, 
including those receiving investigational products, is of 
paramount concern to HHS, as evinced by its position on the 
Patient Bill of Rights, medical data privacy, and the 
allocation of human organs for transplantation. HHS believes 
that exceptions for informed consent should apply rarely. We 
believe that the President's Executive order and the new FDA 
interim rule provide a sound framework for addressing 
exceptional circumstances arising in the context of military 
options.
    Normally, before a sponsor can initiate clinical testing of 
an unapproved product or an approved product intended for a new 
use, an investigational new drug application must be filed with 
FDA. The IND application format calls for information that is 
pertinent to protecting the rights and safety of human research 
subjects, including the requirement for obtaining their written 
informed consent.
    In December 1990, motivated by concerns about potential 
chemical and biological threats to troops participating in 
Operation Desert Storm, the Department of Defense requested 
that FDA waive the informed consent requirement for use of 
particular investigational products. In response, FDA published 
an interim rule amending its informed consent regulations such 
that the Commissioner of Food and Drugs, given appropriate 
evidence, could determine that obtaining informed consent from 
military personnel for use of a specific investigational 
product would not be feasible in certain circumstances and to 
grant a waiver from the requirement for obtaining consent.
    Shortly thereafter, the Commissioner approved waiver 
requests from DOD for use of pyridostigmine bromide tablets and 
botulinum toxoid vaccine. The aftermath of these decisions has 
been subject to intensive examination. The President's Advisory 
Committee on Gulf War Veterans' Illness, deliberating during 
1996 and 1997, described a number of shortcomings in DOD use of 
investigational products during the Persian Gulf war and 
recommended that FDA revisit the interim rule to address, among 
other things, the adequacy of information disclosure to service 
personnel, recordkeeping and long-term followup of individuals 
who received investigational products. An independent 
evaluation by FDA identified significant deviations from 
applicable regulations.
    In July 1997, FDA published a request for comments on the 
1990 interim rule. The responses pointed out significant areas 
that needed to be strengthened, including the following: 
Provision of information about an investigational product 
before its use; followup to assess whether adverse health 
consequences ensue from use of the investigational product, and 
if so, to determine their nature and extent; oversight and 
accountability when investigational products are used; and 
involvement of non-DOD personnel in decisions to use 
investigational products without informed consent. All of these 
topics are covered in the new FDA interim rule.
    The Strom Thurmond National Defense Authorization Act 
answered in the affirmative the question of whether waiver of 
informed consent in military operations ever is appropriate. As 
a consequence of that statute, only the President may waive the 
informed consent requirement for military personnel engaged in 
particular military operations. Moreover, he may make such a 
waiver only if he determines in writing that obtaining consent 
is not feasible, is contrary to the best interest of the 
military member or is not in the interest of national security.
    If his determination be based on grounds that it is 
infeasible or contrary to the best interest of the military 
member, the President must apply the standards and criteria set 
forth in the new FDA interim rule.
    On October 5, 1999, FDA published the new interim rule. It 
requires the Secretary of Defense to certify and document to 
the President that the standards and criteria in the rule have 
been met, including, one, that the medical risk that could be 
encountered during the military operation is outweighed by the 
expected benefits of the investigational product; two, that 
military personnel may be subject to a chemical, biological, 
nuclear or other exposure likely to produce death or serious 
injuries; and, three, that a satisfactory alternative 
therapeutic or preventive treatment is not available and that 
voluntary participation could significantly risk the health of 
individual service members and threaten the military mission.
    The interim rule also requires that each member involved in 
the military operation be given, prior to the administration of 
the investigational product, a written information sheet 
including information on the investigational product, the risks 
and benefits of its use, potential side effects and other 
information about the appropriate use of the product; that DOD 
provide, consistent with classification requirements, public 
notice in the Federal Register describing each Presidential 
determination to waive informed consent, a summary of current 
scientific information on the product or products involved, and 
other pertinent information; and that DOD train medical 
personnel and potential recipients regarding the specific 
investigational product prior to its use.
    Further, DOD must certify and document that it will provide 
adequate followup to identify and assess beneficial or adverse 
health consequences that result from the use of the product and 
that it is pursuing drug development and marketing approval for 
the investigational product with due diligence. And the new 
interim rule provides for FDA to complete its review of the 
proposed protocol for use of the investigational product before 
that protocol may be implemented.
    FDA also can contribute in other ways to DOD's mandate to 
protect military personnel from medical risks associated with 
military operations. FDA is collaborating with DOD in its 
efforts to develop approved products for military need, thereby 
obviating the need to use these products while they are still 
in the investigational stage.
    Also, mindful that the traditional efficacy studies 
sometimes are not feasible or cannot be conducted ethically 
with human research subjects, FDA recently issued a public 
comment a proposed rule that would allow the use of animal 
testing data as the primary basis for human products approval 
under carefully limited circumstances.
    Mr. Chairman, HHS learned important lessons from its 
experience with the waiver of informed consent during the 
Persian Gulf war, and we are putting those lessons to work as 
we prepare for future exigencies, both military and domestic.
    I will be pleased to respond as best I can to whatever 
questions you may have.
    Mr. Shays. Thank you.
    [The prepared statement of Mr. Raub follows:]
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    Mr. Shays. Mr. Sanders.
    Mr. Sanders. Thank you, Mr. Chairman. I'm going to have to 
apologize because there's a markup down the hall in the Banking 
Committee that I have got to be involved in.
    I applaud you for holding this important hearing. I have 
long been concerned about pyridostigmine bromide, the possible 
impact this had on Gulf war illness, the role of DOD, informed 
consent and so forth and so on. I will be back as soon as I 
can, but I just want to thank our guests for being with us 
today, and I will try to be back as soon as I can.
    Mr. Shays. Thank you, Mr. Sanders.
    Mr. Spotila, according to your testimony, you said U.S. 
policy is that it will only administer products approved for 
their intended use by FDA and that only in very rare 
circumstances will deployed military personnel be given 
investigational products. You also said in most of these 
situations informed consent will be obtained. And you also 
said, to further narrow the use of waivers, and I am not doing 
a direct quote, the Executive order also commits the President 
to consider FDA standards and criteria even when deciding on 
waivers requested solely on national security grounds. I have a 
number of questions I want to ask you regarding this.
    How does the Executive order ensure use of investigational 
products by DOD will in fact be rare?
    Mr. Spotila. There are two aspects of that, Mr. Chairman. 
It sets the policy that you have actually quoted from my 
testimony, that we should use these as rarely as possible and 
we should do it only with the health of our troops and the 
security of our country as the guiding principle.
    From an oversight standpoint, OMB works with the Department 
of Defense and with FDA as needed to coordinate the process of 
implementing this Executive order. We have obviously a 
responsibility on the part of those particular departments to 
carry out the policy that the President has set. When we're 
dealing with investigational drugs, the general rule is that 
informed consent is needed, and in the event that the Secretary 
of Defense feels that a waiver of informed consent is 
appropriate, then the procedures described in the order would 
go into effect and need to be complied with.
    Mr. Shays. How do you--and I'm going to be asking you 
basically five questions and then, Dr. Bailey, Dr. Raub, I'd be 
happy to have you respond to any of the questions that I have 
asked.
    How do you reconcile the apparent conflict between a policy 
that requires informed consent and the military policy that 
appears to require mandatory, universal use of every 
investigational product for force protection?
    Mr. Spotila. I'm not sure if I'm following your question, 
Mr. Chairman.
    Mr. Shays. Well, I guess the bottom line is, there's a 
gigantic conflict between informed consent and the military 
policy that requires mandatory universal use, and I don't see 
how we're going to reconcile that. I mean, I'm responding 
really to the concept that it is going to be rare. I don't 
think it is going to be rare. We're in a whole new world right 
now.
    Mr. Spotila. It is difficult to tell how rare it would be, 
because it is difficult to know what the threat is. If the 
threat is greater, then we may be faced with more of these 
circumstances.
    When drugs are approved, of course, DOD has always been 
able to require their mandatory administration. All servicemen 
receive shots. We all know that. When the drug is 
investigational, then we're in a different situation, and there 
either informed consent is needed or a waiver must be obtained. 
We would hope that we don't have a great need for this or won't 
going forward, but we have to be prepared for the contingency.
    Mr. Shays. I guess really what I'm focused on is that 
either the requests are going to be rare or the requests won't 
be, but the granting of those requests will be rare. I happen 
not to believe--I happen to believe the requests will not be 
rare. I think they will be coming quite often. So I then make 
an assumption that you believe that these requests will be 
denied.
    Mr. Spotila. We would hope that the safeguards and the 
procedures that are set forth in the order which require review 
at several different levels, including close coordination with 
the FDA and then a review by the President's national security 
and science advisers, that all of these steps will reduce 
greatly the possibility that a request will actually get to the 
President that is not well supported. The President certainly 
reserves his authority not to grant a request once it comes to 
him for a waiver of informed consent.
    Mr. Shays. Thank you. How would the President know whether 
DOD is complying with the terms and conditions of a waiver such 
as recordkeeping and adverse event reporting?
    Mr. Spotila. He will rely on the Secretary of Defense to 
comply with his responsibilities, with FDA to comply with its 
responsibilities and I'm sure with OMB to use its oversight 
role. We have built in a number of levels of safeguard and 
monitoring. We note that the Department of Defense Inspector 
General, for example, as I indicated in my testimony, will also 
be involved in oversight. So the President is really going to 
rely on these oversight mechanisms.
    Mr. Shays. Under the Executive order, what indicators would 
the President need to see to be persuaded DOD has pursued 
research and full FDA approval of an investigational product 
and not delayed expensive clinical studies knowing the waiver 
process would be available on the eve of war?
    Mr. Spotila. He will rely on the certifications he receives 
and the recommendations of his own advisers, his national 
security and science advisers in assessing what DOD has done 
and whether it's sufficient.
    The real key is that, certainly from our standpoint, that 
this work be done in advance so that the President is not put 
in the difficult position of facing the need to administer a 
drug when work has not been done in advance, work that perhaps 
should have been for the protection of our troops. Ultimately, 
he's going to make the decision he has to make, but we all 
certainly feel a responsibility to work with DOD and FDA to try 
to make sure that they do plan in advance and reduce the number 
of instances where this might occur.
    It's also important to recognize that FDA is playing a 
large role in this; this is appropriate given their area of 
responsibilities and expertise.
    Mr. Shays. My sense was, though, in previous hearings that 
we've had, that basically FDA washes their hands of any 
obligation once they allow, for instance--I don't have this 
sense that they feel they have any real responsibility once 
they have allowed DOD to use an investigational drug.
    Mr. Spotila. Under the Executive order they have a greater 
responsibility perhaps than they have exercised in previous 
circumstances, but I certainly would defer to Dr. Raub to 
discuss more specifically how FDA views its ability to help in 
this area.
    Mr. Shays. I'd invite Dr. Bailey or Dr. Raub to respond to 
any of the questions I have asked. Dr. Bailey.
    Dr. Bailey. Well, in regard to how often it would occur, I 
would sincerely hope, and I know the Department hopes, that 
this request for a waiver, which by the way can only be made by 
the Secretary of Defense, the original request, would be very, 
very rare. Unfortunately, you know that potential adversaries, 
perhaps as many as 10 or 12, are engaged in development of or 
have weapons for which we have no other defense but to use or 
to request a waiver for the use of an investigational product 
being it is the only pretreatment that could save lives.
    Mr. Shays. Right. Given the threat out there, given the 
lack of research we have done to provide our soldiers, our 
sailors, our marines, our air force with the kind of protection 
I think DOD envisions, I envision a lot of requests being made 
for off use of various drugs and that it won't be rare. I see 
that happening, but I could be wrong.
    Dr. Bailey. Well, I think if we look at the No. 1 threat at 
this point, which is anthrax, that is not an investigational 
new product. Fortunately, that is an FDA licensed product that 
has been licensed for many, many years. Furthermore--so anthrax 
would be one of our major weapons of mass destruction that we 
are looking for protection for our troops in terms of medical 
vaccine.
    In terms of pretreatment and investigational new drugs, 
most investigational new drugs are, in fact, not mandatory and 
are under research and are working toward full licensure. We 
also--we look at pyridostigmine, we have $20 million--almost 
$20 million worth of research ongoing and are continuing to 
look at safety and efficacy of that pretreatment, but, again, 
keeping in mind that it is the only pretreatment that could 
save the lives of our troops were they exposed to soman.
    Mr. Shays. Do you want to make a comment, Mr. Raub?
    Mr. Raub. Just several comments, Mr. Chairman, one on the 
issue of the likelihood that requests will be rare and 
approvals rare as well. I think we need to keep in mind that, 
by definition, this could not cover all investigational 
products in that they cover a considerable spectrum from some 
of the very first uses in human subjects through products that 
are well along in clinical development. The standards----
    Mr. Shays. I'm sorry, you lost me in the first part. What's 
your point? I'm sorry.
    Mr. Raub. Well, there's what I'll call a maturity or a 
ripeness of an investigational product, that something can be 
labeled investigational product but only have just begun in 
human testing, and, therefore, there is enough evidence of 
efficacy to make it a plausible candidate for this; whereas 
other investigational products may have been several years in 
development, and there'd be a much richer set of information 
for the Secretary of Defense and the Commissioner of Food and 
Drug to consider. So there's quite a spectrum of the state of 
development of investigational products.
    Mr. Shays. Right. And so what's the point, though?
    Mr. Raub. Well, the point is, I think you had expressed the 
concern that this sort of mandated the use of all 
investigational products, and I was just clarifying that it's 
only investigational products that are indeed far enough along 
in development to have a plausible basis of being efficacious.
    Mr. Shays. So your sense is that only the mature ones will 
be given that waiver?
    Mr. Raub. Yes, sir, and I say that because my second point, 
the FDA interim rule lays out 18 different conditions that must 
be fulfilled and certified and documented on this. I view that 
as a quite formidable gauntlet to be run for these products.
    Mr. Shays. In order to be granted a waiver?
    Mr. Raub. To be granted a waiver, yes, sir.
    Mr. Shays. Any other responses?
    Dr. Bailey. I would also like to add that the use in 
military exigencies, tick-borne encephalitis is another example 
of an IND where DOD did not request a waiver of informed 
consent. When we are looking to use an investigational new 
drug, if it is something that can be done ahead of time, not in 
that exigency moment, in fact we will not look for a waiver. We 
will make every effort to obtain appropriate informed consent 
and to work within the protocol as dictated by the FDA.
    Specifically, though, again, when we are faced with a 
product, a weapon of mass destruction such as soman for which 
there's no other treatment, that is the situation in which, 
were our intel to indicate--confirmed intelligence were to 
indicate soman in theater on the battlefield, that is a time 
where we may be faced with having to request a waiver, but I 
see that as being a very rare situation, and I think our TBE, 
tick-borne encephalitis, situation indicates our real desire to 
work either with FDA-licensed products or to work within the 
standards for INDs.
    Mr. Shays. OK. Even though I'm not sure how much I want to 
take the committee's time to go down the whole anthrax issue, 
but, bottom line, we were using it for a particular use with 
potentially about 300 people a year, and DOD decided to use it, 
administer it to potentially 2 million of our American 
soldiers, sailors, marines and air force, as an antidote to 
military use, presenting itself very differently than it would 
present itself to the 300 who traditionally would get it every 
year, airborne versus----
    Dr. Bailey. Cutaneous. Well, let me just speak very briefly 
to that. Because I agree that's a whole other hearing, but in 
fact we again have studied--and we must, I think, delineate for 
this hearing that the anthrax vaccine is a licensed vaccine. 
Yes, it was used for myasthenia gravis over the years, but we 
also have used it with our researchers for years in Fort 
Detrick.
    And, furthermore, I want to quote from March 13, 1997, when 
Michael Friedman--Dr. Michael Friedman spoke from HHS, saying 
that as far as the issue about cutaneous versus inhalation, we 
know that our product is effective in Rhesus monkeys against--
90 percent effective, 90 to 95 percent effective against 
inhalation anthrax, and again where our troop is exposed it is 
virtually 100 percent deadly were they not protected with the 
vaccine.
    Mr. Shays. I just want to say you keep making that point, 
and that's why I question about the requests will be rare. I 
could give you and you could give me potentially 50 biological 
agents that could be that kind of threat, and then you will try 
to find an antidote to each one. I'm sorry. That doesn't make 
me feel it's going to be rare. I am not saying--I am raising 
the question of whether the requests will be rare and whether 
the granting of the waiver will be rare, and my only issue is 
with the concept that I should feel comfortable that it will be 
rare. I don't think it will be, but time will tell.
    Dr. Bailey. Mr. Chairman, could I just add to the last 
point that you had brought up about the cutaneous versus the 
inhalation? In that March 1997, letter, the HHS stated results 
from animal challenge studies have also indicated that 
preexposure, administration of anthrax protects against 
inhalation anthrax. So we feel we're comfortable with that 
particular vaccine which is not an IND and, of course, would 
not involve a waiver.
    Specifically about looking at it in rare instances, it is 
the rare instance where we would be faced with not only any 
CBW, any chemical biological warfare agent, but specifically 
soman in the case of PB, an investigational product. That is 
hopefully something we will not be encountering in the future, 
and it would be a very rare instance where we would have to 
look for a waiver and informed consent, and I would hope by 
that time we would have it licensed for this use.
    Mr. Shays. Thank you.
    Mr. Allen.
    Mr. Allen. Thank you. Thank you all for being here. I 
regret that I only have a few minutes. I am sort of running 
between one thing and another.
    But, Dr. Bailey, I have--I want to take you back. This may 
seem a little bit off the point of what we're discussing today, 
but I assure you I'm going to bring it back.
    In your--in previous testimony before--before this 
committee, I believe, you indicated that with respect to the 
anthrax vaccine there was no evidence of anaphylactic reactions 
to that vaccine. Our sources at Dover Air Force Base tell us 
there are 64--at least 64 cases of anaphylactic reactions and--
but that these severe reactions are not being described, 
reported, brought to the attention of the appropriate 
officials.
    Second point that we're hearing is that troops with 
reactions initially were sent to Walter Reed for further study 
where they could receive a 1-year waiver from vaccination if 
doctors agreed that they had had a severe reaction. However, 
that policy was changed to refer them instead to Andrews Air 
Force Base where the perception is service members are much 
less likely to get a 1-year waiver because it is an air base 
with a military mission and not a military hospital with a 
medical mission.
    In March--you testified before the subcommittee in March 
that you had seen no evidence of severe reactions to the 
vaccine. Have you learned anything either related to Dover or 
anywhere else in the country that would change your testimony?
    Dr. Bailey. Well, first of all, the reporting is done 
through the vaccine adverse event reporting system, which is 
part of CDC. That is true for all vaccines, and that is the 
reporting system we are using with the anthrax vaccine program. 
The specific referral to anthrax or to anaphylactic reaction 
should have been related to the outcome of death in regard to 
an anaphylactic toxic reaction. Specifically----
    Mr. Allen. I understood the word meant a severe or systemic 
reaction.
    Dr. Bailey. It does. It can lead to death. My referral was 
fortunately in our program, as opposed to other programs and 
other vaccines, where unfortunately occasionally you have an 
anaphylactic reaction that results in death. That has not 
occurred--we have had no deaths in a program which now includes 
over 340,000 troops and over a million doses of vaccine 
administered. So, again, we feel it is very safe.
    Now, we do report through VAERS, and at this point, we have 
somewhat over 300 reports to VAERS, that's the vaccine adverse 
reaction reporting system, and--but only about 20 of those are 
the severe type that would require hospitalization or a loss of 
duty time. I think the main message would be that the adverse 
reactions we are seeing are mostly localized and are very much 
in line with the vaccines that are given here in this country 
to children or typhoid, tetanus, diptheria, the kinds of 
reactions we see with other vaccines.
    Anthrax also does have some reactions, but they are very 
much in line with all other vaccines that are given.
    Mr. Allen. Let me sort of come from that to--I'm sorry, I 
can't recall who was testifying, but it was a hearing on--
before the Armed Services Committee on which I also sit, and 
the military brass was lined up at the table, and the question 
was posed whether or not there were some national system for 
tracking adverse reactions to the anthrax vaccine. And the 
response was no, and we don't want to do it essentially because 
we don't do it for any other vaccine, and that--I wish I could 
cite you chapter and verse, but that was the response that was 
fairly uniform among the three or four military officers who 
were testifying at that hearing, and I didn't come prepared 
with it.
    So here's my question. How would--and you can correct me on 
that if you'd like--but what I'm leading to is, how would DOD 
monitor adverse reactions in a comprehensive way the service 
members may experience as a result of taking an investigational 
drug? I will tell you as a Member of Congress sitting here 
listening to what I've heard at the various hearings I have 
been to, it's hard for me to have confidence that the 
military's really committed to a thorough reporting of adverse 
reactions, and I'll dump all of that in your lap for your 
response.
    Dr. Bailey. OK. First, let me say I've had five anthrax 
shots, and I can punch in on the computer at the Pentagon or I 
have done it out in the desert under a tent in the Persian 
Gulf, said--put my name in, put in my Social Security number 
and see what comes up. It tells exactly how many I've had and 
when my next one is due, and it will tell me if I'm late by 2 
weeks. So we have a very, very specific tracking system.
    As part of the tracking----
    Mr. Allen. Wait a minute. That's totally different from 
whether you're actually accumulating information in Washington 
about adverse reactions.
    Dr. Bailey. OK. I would also add, first of all, in regard 
to your first statement about remembering what happened and the 
first answer that was given, I believe what you're referring to 
is the refusal policy. Because that is something that I do 
recall that the services, each of them testified that that is 
not something that is done for any order or any vaccine, and 
that is what they are not tracking.
    What I'm trying to indicate to you is that we are tracking 
very specifically all of the anthrax immunizations, and we 
clearly do want to look for adverse reactions. In fact, we have 
a project at Tripler involving about 600 people who are all 
medics themselves or health care administrators that 
specifically ask for any adverse reaction. If it's an ingrown 
toenail and you think it's not related to this vaccine, we 
still want to know any medical problem you have. That is going 
after those adverse reactions in a very constructive way.
    We also are specifically part of the same program that all 
vaccines participate in in VAERS with CDC. So we are 
aggressively tracking this and look with our information 
systems to even better products that will allow us even greater 
clinical knowledge about the vaccines we give.
    Mr. Allen. So are you confident that you have access--you 
can now say there are 20 or however many cases of severe, 
systemic reactions to the anthrax vaccine, and when you give 
that number, are you confident that you've got all the cases?
    Dr. Bailey. I will provide for the record the specific 
number and--but, yes, I am confident in our ability to track 
adverse reactions.
    Mr. Allen. Thank you.
    Thank you, Mr. Chairman.
    Mr. Shays. Thank you.
    I'd be happy to recognize Mr. Towns, who is my former 
ranking member, and I miss him a lot.
    Mr. Towns. Thank you very much. Thank you, Mr. Chairman, 
and also, let me thank all of you for your testimony.
    You know, I have got sort of basic kinds of questions. How 
would DOD ensure that the service members receive the proper 
dosages of investigational drugs in a timely manner? I mean, 
how? Could you assure me of that?
    You, Ms. Bailey, go ahead. It's fine.
    Dr. Bailey. Dr. Bailey.
    Mr. Towns. Dr. Bailey, I'm sorry.
    Dr. Bailey. In fact, it may be helpful for you to know some 
of the changes we've made in one of the investigational new 
drugs that we are all focused on, and that is pyridostigmine. 
During the Gulf war we gave out pyridostigmine which had to be 
given at least 8 hours before an attack. Again, soman is a 
deadly, lethal agent, and had we not provided a pretreatment, 
our usual medications, our medics were not able to provide any 
treatment that would have saved the lives of our troops. So we 
had to use pyridostigmine.
    It was specifically given in a--in this packet form, and 
the directions for use said: Commence taking only when ordered 
by your commander, take one every 8 hours, and it is dangerous 
to receive the stated dose.
    Now, the problem was that I think now, in retrospect, we 
all realize that was not enough information in this format. We 
did have other information provided through commanders' calls 
and that was the line responsibility. But at this time I would 
like to report that in fact we have changed what the packet 
includes, and the packet now includes the same information I 
stated before, but it also has on the back, and I just, because 
this I think is very essential to what we're talking about, 
would read to you that it has warnings about if you have 
asthma, for instance, or are pregnant or taking medicine for 
high blood pressure, you would see your unit doctor before 
taking pyridostigmine.
    It also says that PB is for military use only. It is not 
approved by the FDA for marketing as a poison gas antidote and 
before using read the enclosed information, and there is an 
entire insert which has much more information about the 
effects, about warnings, about when not to take PB, how 
specifically to take it and other information about the drug. 
So we feel that plus the warnings that are on the record will 
allow us to have better information to the troops.
    Mr. Shays. Would you submit those for the record, please?
    Dr. Bailey. I will get you those for the record, sir.
    Mr. Shays. Also, the study, Tripler study, when will that 
be available?
    Dr. Bailey. That is an ongoing study. It is ongoing as we 
speak looking at those adverse effects, and I will get you that 
as well.
    Mr. Shays. Thank you very much.
    Mr. Towns. Let me say--and I'm sure you've probably heard 
it even more than I have heard it. What people are generally 
saying is that this is really research going on and that the 
physicians who are involved in it, that they're so wrapped up 
in their research that sometimes they're not looking at the 
day-to-day conditions of the patient in terms of how the 
patient's condition is changing, whatever, and that the 
structure is bad, that you need to have a physician that's just 
going to look at the patient in terms of the patient's 
reaction. Because what they're saying, and I know you've heard 
it, that the doctor is so involved in the research aspects, 
because this thing is research and, of course, you need to have 
somebody else to look at the other aspects, because if I'm 
involved in the research, I'm more attuned to that, then that's 
what I'm interested in, and sometimes I might forget some other 
things, and there needs to be someone to look at the day-to-day 
activities of the patient in terms of whether they're 
responding, what kind of way, and so there's a lot of criticism 
about the structure. Could you respond to that? Anybody, 
anybody.
    Dr. Bailey. Well, I can assure you that this is not 
research, that the use of this investigational new drug as a 
pretreatment for the nerve gas soman will only be used in those 
rare circumstances where we have no other method for protecting 
the life of the troop member. It is not research. Research 
generally implies that you're looking for licensure for 
another----
    Mr. Towns. You have heard this comment, haven't you?
    Dr. Bailey. Yes, and I understand what you are saying, and 
I would just assure you that our medics, our physicians, our 
medics in the field, it is their prime responsibility to 
provide force health protection, and we in health affairs, even 
while we are doing policy, are aware of our responsibility to 
that mission, not to the mission of research.
    I would also add that we do have oversight by the Armed 
Forces Epidemiologic Board which makes recommendations to me 
and to the Surgeons General, and that is a civilian oversight 
board. We often also involve the Institute of Medicine, as you 
know, the President's advisory committee. So there are many 
civilian oversight organizations that provide us with I believe 
the kind of medical oversight that you would be more 
comfortable with.
    Mr. Raub. Mr. Towns, might I just add, make it more 
broadly? I, too, have heard the comments. I believe they may be 
based in part on a less than full appreciation of the 
safeguards already in place or the ones more recently put into 
place as a result of the Executive order and FDA's new interim 
rule. For example, many products are under development by the 
Department of Defense as investigational products, and are 
subject to all of the requirements of FDA for investigational 
products, including informed consent, and so there are 
mechanisms within the Department of Defense as well as the FDA 
governing those, and those don't change.
    In those instances where, under the new rules, the 
President approves an investigational product for use without 
informed consent as a basis of either therapy or prevention, as 
I indicated in my earlier comment to the chairman, I believe 
the conditions are so specific and so stringent that nothing 
approaching a frivolous or overambitious use of that product 
could pass. And I don't believe the Department of Defense would 
in fact propose such.
    So we are confident. We believe we need to work harder to 
ensure that people understand the nature and the strength of 
the protections that are in place.
    Mr. Towns. Thank you very much.
    You want to add anything there?
    Mr. Spotila. No. I think that I would agree completely with 
Dr. Raub's and Dr. Bailey's treatment of this.
    Mr. Towns. I want to understand one thing very clearly, how 
this new system will work in practice, especially when things 
get hectic in a wartime situation where things are really 
hectic. Under this process, it appears DOD is supposed to 
develop a waiver request in consultation with FDA. You know, 
what does this really mean? What does it really mean?
    Mr. Spotila. The President has directed that FDA be 
involved in the preparation of the waiver request precisely so 
that it can proceed more quickly and so that it can be 
coordinated more closely with FDA's traditional oversight of 
the use of investigational drugs. That is a recognition that 
time could be a factor. And so the order directs DOD to be 
looking farther out in advance both from an intelligence 
standpoint and from a development of new products standpoint, 
so that we don't find ourselves at the last minute having to 
make decisions. And then in setting up the particular process 
for a waiver request, it involves FDA at a very early stage and 
throughout the proceedings precisely so we get their input and 
so that the President can be as well informed as possible 
before making any decision about a waiver of informed consent.
    Mr. Towns. Go ahead.
    Dr. Bailey. I may have more information than you would want 
to know, but you can stop me at any point. And let me say, we 
are in the process, first of all, of developing this protocol. 
Now that the Executive order is in place, we're working, 
interagency, all of us, to develop a protocol that will adhere 
to the criteria which is appropriate.
    Specifically, we're adding information on the Executive 
order to all of our training classes, our pamphlets, our 
manuals and other publications that are currently provided on 
chemical biological countermeasures. That will assure that the 
military personnel receive as part of their CBW training 
information on the reasons why INDs are used and may be needed. 
We are adding information to the medical providers and training 
classes as well, to their pamphlets, to their training on CBW, 
and this will assure that the medical providers themselves are 
aware of all the issues and are able to answer the questions of 
the service members.
    Specifically with respect to pyridostigmine, pretreatment, 
as you know, for soman, I have directed that the information 
sheets which have been approved by the FDA be included in all 
of our training manuals.
    Mr. Towns. Let me ask you this. I think I'm having trouble. 
Let me say what I really want to know. Does the FDA have the 
authority to prevent a DOD waiver request from going to the 
President? That's really what I want to know.
    Mr. Raub. Yes, sir, it does. The way the interim rule is 
established, among other things, the FDA must determine that 
this investigational product is, in fact, at an appropriate 
stage to be used in that way, that there's a reasonable basis 
to expect it will be effective, and there is solid basis to 
expect that it will be safe. So if it doesn't meet what I'll 
call a test of maturity as an investigational product the FDA 
does not have a basis to make that determination.
    Mr. Towns. Thank you very much.
    Thank you very much, Mr. Chairman.
    Mr. Shays. Thank you, Mr. Towns.
    Dr. Bailey, how would you make sure recordkeeping and 
adverse reporting requirements are observed in the field?
    Dr. Bailey. Fortunately, a great deal has happened since 
the lessons we learned in the Gulf war. We are now developing 
information systems that I think will provide us with the 
capability to do the kind of clinical tracking that I think we 
all know would be appropriate, including adverse reactions.
    We have the next generation of the composite health care 
records, CHCS2, that up to a third of our organization will 
have in place by this coming summer. We also have for the 
battlefield the theater management information program which 
will assure us better tracking of situations, medical 
situations in theater. And we also recently have developed and 
are finally fielding the personal information carriers, which, 
as you may be aware--fortunately, that's not it, but, 
fortunately, this is.
    You know that we've carried dog tags for years, and those 
dog tags, unfortunately, were notched so that they could be 
placed on the body of a service member that did not make it, 
and it didn't really provide much else except identification. 
This is the PIC, which is a Personal Information Carrier. This 
is the one that we have now chosen and are fielding, and as you 
can see it's about the size of a dog tag, in fact smaller.
    And it would be interesting for you to see it sometimes, 
the information that is carried on here. There are about 16 
megabytes--there are 16 megabytes on here. We can get off of 
here not only dental records, not only the usual clinical 
information about adverse reactions, but we can put on here an 
MRI, CT scan, x rays, all of this on a PIC so that I think each 
member will be carrying this Personal Information Carrier with 
that medical data on it. And I think if you combine that with 
the theater management program and the involvement of our CHCS2 
you're going to find better and better recordkeeping.
    Mr. Shays. Thank you. The last question I would like to ask 
you is really a response to Michael Friedman regarding the--to 
the Food and Drug Administration dated October 29, 1997. It's 
from Dr. Edward Martin, Acting Assistant Secretary of Defense, 
and it also includes DOD comments on questions posed in the 
Federal Registry notice. And in regards to the issue dealing 
with medical treatment and medical research, does DOD consider 
the use of investigational products as force protection against 
chemical weapons and biological weapons as research or merely 
the off-label practice of medicine?
    Dr. Bailey. I know the line in the letter you're referring 
to, and I know the weight that it carried. Yes, I believe as a 
physician that we are practicing the best medicine available to 
us to protect our troops.
    Mr. Shays. So why apply for a waiver in that circumstance?
    Dr. Bailey. I think, generally speaking, and I think one of 
my colleagues here may want to comment on this, but, generally 
speaking, as a physician, for instance, I am allowed to use a 
particular medication for a particular patient off label as a 
physician without going through a waiver of informed consent. 
However, I think that would be impractical when we're looking 
at thousands or hundreds of thousands of troops, besides which 
I think personally that would be inappropriate, and that in 
fact what this Executive order puts in place is the appropriate 
methodology for dealing with an investigational new drug.
    Mr. Shays. Mr. Raub.
    Mr. Raub. I'll add the point, Mr. Chairman, that, by its 
nature, when an investigational product is in clinical 
investigation, it simultaneously involves both patient care and 
research. In other areas, for example, the development and 
evaluation of new cancer drugs, we often say that the best 
available therapy many times is to be part of an experimental 
protocol. So we recognize all along that the physicians 
involved have the dual responsibility of their health care role 
and the question of research.
    The vast majority of investigational new drugs are subject 
to those dual types of considerations. It's only this 
particular exception that is embodied in the Executive order 
and in the new FDA interim rule that contemplates the situation 
of an investigational drug far enough along for us to know a 
lot about it to be used, in effect, as a therapeutic or 
preventive intervention without informed consent because of the 
expected health benefits of that.
    Mr. Shays. I guess what I'm trying to understand is the 
military--the DOD's attitude to off-label drugs and whether or 
not DOD is going to make the requests rare by not making the 
request because it's off label and, therefore, can still be 
used and not considered an investigational drug. I mean, that's 
one way to make it rare, is never ask but use it.
    Dr. Bailey. If soman is not used on tomorrow's battlefield, 
we will not be asking for the waiver for PB.
    Mr. Shays. Say that again.
    Dr. Bailey. If soman were used, we would have no other 
option perhaps but to look for waiver of the informed consent. 
I would hope that we would have enough intelligence provided to 
us to use any product, including the countermeasures we are 
discussing, ahead of time and to do that with informed consent, 
but the battlefield situation may not allow for that.
    Mr. Shays. Be patient here. I just want to have some sense 
of, if DOD considers it medical treatment and not research, do 
they feel obligated to ask for waiver?
    Dr. Bailey. Well, I think there are, again, several ways in 
which investigational new products are used, and I think you've 
heard them described here. They may be used in a research 
protocol. They may be used off label because they've been shown 
to be efficacious, because they're mature enough in the 
developmental process and moving toward full licensure.
    I would just say that if it is an IND we will follow to the 
letter the rules set out in the Executive order and adhere to 
those rules and standards according to the FDA requirements and 
that does require perhaps in a military exigency a waiver of 
informed consent.
    Mr. Shays. A lot of wiggle room here.
    Dr. Raub, can you help me out here? I feel like this issue 
leaves such an open door. Is it possible that any off-label use 
of a drug can be used by DOD simply by the fact they deem it 
medical treatment?
    Mr. Raub. Just as a bit of background first, Mr. Chairman, 
if I may. The notion of an off-label use by definition applies 
to a product that's already approved for something, so it will 
have gone through the normal FDA regulatory process first, 
especially for safety and for efficacy against some 
particular----
    Mr. Shays. But such as pyridostigmine bromide, that was off 
label, correct?
    Mr. Raub. Yes.
    Mr. Shays. OK. But they did ask for a waiver.
    Mr. Raub. Correct.
    Mr. Shays. But, under Dr. Bailey's response, I feel that 
she next time could say, no, we don't have to.
    Mr. Raub. The second background point I wanted to make is 
that, under its normal practice, the FDA is not in the position 
of regulating the practice of medicine. Its oversight is 
limited to the sponsors of investigational products. And the 
medical community in general, as Dr. Bailey indicated, has the 
license to make off-label use in particular circumstances.
    When it comes to an institutional policy I think some of 
our concerns arise that it is not just one-by-one physician 
decisions with individual patients but rather some policy, and 
we believe the Executive order and the new interim rule go a 
long way to regularizing how that would be done.
    Mr. Shays. I just want to know as it relates to off-label 
use of drugs. I want to know how this Executive order 
specifically relates to off-label use of drugs. I am not saying 
it's not there. I just want to know the answer to the question. 
I'm really not getting an answer.
    Mr. Raub. Again, the Executive order is focused on those 
instances where in a military operation the Department of 
Defense would be seeking the waiver of informed consent. So it 
is limited to that situation.
    Mr. Shays. So the issue is that it is more than off label. 
How would this Executive order affect PB, for instance? Let's 
go back. How would it have affected it? Under Dr. Bailey's 
response, she would not have had to ask for informed consent. 
She would not have had to ask for a waiver.
    Mr. Raub. I wasn't interpreting Dr. Bailey's response that 
way.
    Dr. Bailey. Nor was it intended that way, Mr. Chairman. My 
intent was describing the various ways in which INDs are used, 
and I think that's what we have attempted to share with you. As 
a physician for a particular patient in a particular situation, 
I would be allowed to use a specific medication off label. I 
feel that is not clearly the situation in a broad policy effort 
as we would be making to protect our troops and their health 
protection in a military exigency. So I did not mean to imply 
that.
    Mr. Shays. I can live with that answer. I'm going to put it 
in my words and tell me if it's accurate. Obviously, a 
physician is free to use an off-label use of a drug in any way 
they see fit, correct, if they believe it is dealing with a 
medical necessity. What I'm hearing you say, Dr. Bailey, is 
that if you decide to make the use of this drug universal for 
off-label purposes that you feel the obligation to ask for a 
waiver?
    Dr. Bailey. To adhere to the IND requirements.
    Mr. Shays. What is that?
    Dr. Bailey. Or if it is not--if it is not needed, if the 
waiver is not needed but we are going to use investigational 
new drugs, that we adhere to all the standards for any IND, 
including informed consent of the individuals.
    Mr. Shays. Let me back up. Technically, under your answer, 
you would not have to ask--have asked for a waiver on PB; is 
that correct?
    Dr. Bailey. If I adhered to all the standards of an IND, 
yes, I could use PB as an investigational new drug if we went 
through all of the criteria for an IND, and we would do so.
    Mr. Shays. Including getting informed consent?
    Dr. Bailey. Yes.
    Mr. Shays. I'm going to yield to my counsel.
    Mr. Halloran. Who manufactures pyridostigmine bromide?
    Dr. Bailey. It is a Roche product. Dufar, which is a Dutch 
company.
    Mr. Halloran. And so, for purposes of FDA regulation, 
they're the regulated entity. How is it that DOD then would be 
conducting an IND or applying for an IND or for a use of 
someone else's drug?
    Dr. Bailey. I would need to provide you an answer for the 
record on that.
    Mr. Raub. May I just add, though, that is a common practice 
where someone other than the manufacturer of an agent may be 
the sponsor of an IND. Some of the agencies of our own 
department, for example, the National Cancer Institute, may on 
occasion be the holder of the IND application.
    Mr. Halloran. What evidence or association between a 
manufacturer and the IND holder would FDA require?
    Mr. Raub. Well, the FDA would require considerable 
information about, indeed, the involvement of the manufacturer, 
certainly the manufacturer's normal requirements for the purity 
of its products and all the other things are taken into 
account.
    But in that situation I described, the other entity has the 
responsibility for the design and conduct of whatever proposed 
clinical studies are there, and many times that occurs when the 
manufacturer may not have its own commercial interests at high 
enough levels to pursue that development. But in the interest 
of the public such as, again, cancer drug development, an 
agency of the government may choose to push that along. And in 
the same way the Department of Defense may be the holder of the 
IND because it sees the need for the particular military 
circumstance.
    In the case of PB, I think we all agree that the most 
desirable outcome would be for the current IND work to 
continue, to come to fruition, and to have a sufficient basis 
for the FDA to be able to approve PB for the indication of 
protection against soman. That would obviate the need to 
exercise the Executive order for that circumstance.
    Mr. Halloran. But would that approval then result in a 
change of the labelling that the manufacturer didn't ask for?
    Mr. Raub. Yes, sir.
    Mr. Halloran. It would.
    Mr. Shays. Mr. Towns.
    Mr. Towns. I just want to sort of clarify something here in 
my own mind. We're talking about investigational, and we're 
talk about the consent and all that, I understand that, and at 
the same time there's mandatory. Now, unless the military's 
changed, mandatory means that there is no consent. I mean, that 
happens, I mean, because after all you're in the military, and 
this is what the decision is, and you better follow it. So, I 
mean, am I correct on that? Because I think that's some of the 
problem here.
    Dr. Bailey. If it's a lawful order and it is mandatory, 
yes, you would follow that. But I would again indicate our 
usage of tick-borne encephalitis. If we are not using--not 
looking for a waiver of informed consent but are going by the 
standards set for an IND, then we would in fact adhere to those 
standards and inform each service member about the product, and 
it would not necessarily be mandatory.
    Mr. Towns. I am not quite clear what you mean. Run it past 
me one more time.
    Dr. Bailey. If a vaccine--if we decide to give a vaccine, 
an order is given that you will take the vaccine, whether it's 
typhoid or malaria or anthrax, for instance, and it is an 
order, regardless of the status of the product, that is a line 
issue, and if it is a lawful order given to a service member, 
then it is a mandatory order regarding--regardless of the 
information that's given. That does not mean, however, that we 
do not try to provide, as in the case of pyridostigmine, all 
the possible information that we can to the service members.
    Mr. Towns. And you do all that and I say no, what happens?
    Dr. Bailey. Then you are subject to administrative and 
disciplinary action if it was a lawful order given and you are 
a member of the U.S. forces.
    Mr. Towns. Thank you.
    Mr. Shays. Just a few more questions here.
    Dr. Raub, how will HHS ensure DOD is living up to the terms 
and the conditions of the waiver? And specifically I want to 
know what enforcement authority or sanctions does FDA or NAH 
have available in the event DOD fails to provide required 
individual information on investigational products or fails to 
maintain medical records?
    Mr. Raub. First of all, Mr. Chairman, FDA has stepped up 
its collaboration with DOD and is trying to build the 
mechanisms where it will be able to get information after the 
waiver that will help it determine, for example, the patterns 
of adverse effects that may be seen and the like.
    Second, the FDA rule requires the Secretary of Defense to 
apprise the President and the Commissioner of any circumstances 
that might change, different from the intended use, that might 
require this being revisited. And, among other things, this 
could be the basis for the FDA withdrawing its certification 
under those circumstances.
    Third, and I think most importantly, because this creates 
the framework through the President and involves, as Mr. 
Spotila indicated, not only the FDA but the expectation that 
DOD's own mechanisms of oversight will be there and the DOD 
Inspector General, we believe that the combination of that with 
FDA's expertise will go a long way to ensuring that the 
adherence after the waiver is consistent with the terms on 
which the waiver was based.
    Mr. Shays. Bottom line, though, what basic authority or 
sanctions does FDA or NAH have? They can withdraw the waiver?
    Mr. Raub. The FDA could recommend to the President that the 
waiver be withdrawn based on certain conditions that had 
occurred, yes, sir.
    Mr. Shays. If DOD does not provide the information FDA 
wants, what can FDA do?
    Mr. Raub. I think the first step FDA would take is working 
directly with the DOD to make very clear what information it 
wants and why and in what timeframe. I'd like to think that 
would be forthcoming; but if it weren't, I think the FDA would 
have an obligation through the Secretary of Health and Human 
Services to go to the President and indicate that the 
information needed to ensure a judgment of compliance needs to 
be in place. And we would look to the chief executive or the 
commander-in-chief to get that information.
    Mr. Spotila. Mr. Chairman, I would add that we're aware 
that there is a need for implementation of this Executive order 
and that includes working out in more detail some of these 
procedures. OMB will be involved with FDA, with HHS and with 
DOD in trying to do that. We recognize there are more details 
that have to be worked out, but I would certainly reaffirm what 
Dr. Raub has said, which is that the President would want us to 
monitor the situation, and certainly if FDA indicated that we 
had this type of problem, we would respond quickly to it.
    Mr. Shays. Who in OMB would monitor this? What unit within 
OMB?
    Mr. Spotila. Well, it will be monitored in two respects. We 
have desk officers who actually work with each of these 
agencies who monitor and maintain lines of communication about 
their various programs. My office, the Office of Information 
and Regulatory Affairs, was instrumental in coordinating the 
interagency process that led to the development of the FDA 
rule, and so we have some involvement, but it is also true as 
the order directly states that the National Security Council 
and the Office of Science and Technology Policy will maintain 
some monitoring as well. So we have both OMB and these other 
executive office entities that will be involved in this.
    Mr. Shays. Thank you.
    Dr. Bailey, I'll just end with you. What obligations do you 
have to FDA?
    Dr. Bailey. To provide--we are specifically charged within 
the Executive order to provide the training and the tracking 
and the information. But I think, as you have heard indicated 
here, we have a strong interagency working relationship to 
develop these protocols. They are under development now so that 
we can assure strict adherence to all the standards.
    Mr. Shays. So I make the assumption that you recognize that 
DOD has an obligation to HHS to respond to their requests and 
to live up to their obligations?
    Dr. Bailey. Absolutely. Yes, sir.
    Mr. Shays. Thank you.
    Any other questions?
    Thank you all very much, very helpful, very interesting.
    Let me just actually conclude by allowing you all to make 
any closing comment you might want to make.
    Mr. Spotila. No comment.
    Mr. Raub. No comment, Mr. Chairman, other than thanking you 
for the opportunity to discuss these issues with you.
    Mr. Shays. Thank you. They're important issues, and your 
testimony was helpful. Thank you.
    At this time, we'll call our second panel, Dr. Arthur 
Caplan, director of the Center for Bioethics, University of 
Pennsylvania; and Dr. Charles McCarthy, senior research fellow, 
Kennedy Institute of Ethics, Georgetown University.
    If you'd stay standing, please, Dr. Caplan, I'll swear you 
in.
    [Witnesses sworn.]
    Mr. Shays. Thank you.
    For the record, both have responded in the affirmative. Dr. 
Caplan, you're first; and I appreciate both of you here.
    Let me say that you have your written testimony. We are 
happy to have you read it, parts of it or all of it, but if you 
want to just respond in general, particularly since you've 
heard the first panel, that might be more helpful. So we'll 
roll with the punches, however you'd like to go.
    OK, Dr. Caplan.

   STATEMENTS OF ARTHUR CAPLAN, PH.D., DIRECTOR, CENTER FOR 
 BIOETHICS, UNIVERSITY OF PENNSYLVANIA; AND CHARLES MCCARTHY, 
  PH.D., SENIOR RESEARCH FELLOW, KENNEDY INSTITUTE OF ETHICS, 
                     GEORGETOWN UNIVERSITY

    Mr. Caplan. OK. Well, I'm going to take the ``just 
respond'' for the interest of time.
    Mr. Shays. Can you put the mic a little closer?
    Mr. Caplan. I'm going to take the strategy of just 
responding with some brief comments, since the testimony is 
there, and thanks for opportunity to address the subcommittee.
    Let me just respond on three areas.
    First, the issue of would a request be rare or frequent and 
is there an adequate set of hurdles. I don't think the set of 
hurdles that's been created is adequate. I think there's some 
reason to think that requests could become very frequent.
    We heard in the earlier panel some of the issues that have 
been dealt with with PB, with anthrax and tick-borne 
encephalitis, but in the world to come of biological warfare in 
particular, genetic engineering is going to open up the 
opportunity for a lot more rapid development of offensive 
weapons, and these are going to trigger attempts to find 
preventive responses, and I think we could be looking at a 
rapid series of requests to undertake preventive measures with 
relatively little information at hand on the part of the 
Department of Defense. And, to be blunt, I think without tough 
FDA requirements, tougher than have been put forward so far, 
the hurdles to get those requests in front of the President are 
not adequate. So I am concerned about the trigger issue.
    The second thing I would say is I'm not convinced yet in 
the Executive order that there is adequate outside independent 
review of those requests by FDA or DOD. Charles comments on 
this in his written testimony.
    In situations where waivers are asked, emergency research, 
for example, where someone suddenly gets a heart attack and 
someone has a bright idea about how to treat them and they're 
not going to be able to consent, we ask for very tough IRB 
review, Institutional Review Board, or Human Experimentation 
Committee review, and I would like to see that provision 
toughened in the interaction between DOD and FDA for outside 
peer review, if you will, and community review.
    The last thing I just wanted to comment on, Mr. Chairman, 
just in the interest of time, is what happens when consent is 
waived. And I think you know that I was a member of the 
Presidential Advisory's Committee on Veterans Gulf War 
Illnesses, and so I feel some obligation to comment here about 
what's in the record for what happens when waivers happen. 
Because things did not happen well from the Gulf war situation, 
and the track record for recordkeeping, followup and disclosure 
might generously be described, I think, as abominable.
    What is laid out in the Executive order and in the backup 
Federal policy and rule so far I do not believe is adequate to 
ensure that if someone is given something without their 
permission they will be followed and tracked and adequately 
monitored to see what harm may have happened if an untoward 
event results from getting a vaccine or a drug or some other 
unapproved intervention. And I might humbly suggest that one 
way to make sure requests are rare and compliance is thorough 
is for some articulation of what a compensation policy might be 
if harm occurs. That hasn't been put on the table. That might 
be the best measure to ensure that requests are going to be 
infrequent to waive informed consent and that if they are 
granted that there's going to be serious tracking of what 
happens to people who don't get to give permission when 
something new is used.
    I said that was my last comment, but I'll add one more just 
because it came up in the discussion. There is this ambivalence 
about is this research. Well, I don't doubt that people who 
gave PB weren't trying to do experiments in the field during 
the Gulf war, but the fact is that when you're using new 
experimental innovations you are then creating an experiment, 
and I think we have an obligation to our military members to 
carefully track and monitor what takes place, if only to learn 
what happened.
    Mr. Chairman, 10 years after the PB was given out, we still 
don't know any more about it than we did 10 years ago. So not--
by not having adequate policy laid out, clear policy requiring 
public presentation of whatever the findings are concerning 
health impacts of situations where things are tried without 
informed consent, we can't learn, and so we find ourselves 
cycling around and around again trying to understand whether 
it's worth the risk to give out these unproven and sometimes 
inadequately tested interventions, not from malice, not from 
ill motives, from good motives, but, nonetheless, that's not 
the public policy that is going to get us where we want to go.
    Mr. Shays. Thank you so much.
    [The prepared statement of Mr. Caplan follows:]
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    Mr. Shays. Dr. McCarthy.
    Mr. McCarthy. Mr. Chairman, I want to thank you and the 
committee for holding these hearings, and inviting us to 
testify. Addressing these issues at time when we are not in 
national crisis is of utmost importance, and I congratulate you 
for doing that.
    You have a copy of my written testimony, and like Dr. 
Caplan, I see no reason to read most of that to you.
    I served on the committee that was advising the FDA 
Commissioner back in 1990 when PB and BT were both under 
consideration and several other drugs that were subsequently 
dropped from the waiver request. I think the questions you 
asked the previous panel are still pertinent and answers are 
still somewhat murky, particularly the answers to your question 
concerning the off-labele use of approved drugs. In fact, I 
think it would be very rare that we would not have an off-label 
use of drugs in a time of military crisis.
    I consider the situation in which these drugs for toxins 
are used in warfare to be so different from the kind of use 
that would be made in a hospital or in a laboratory where 
workers are accidentally exposed to a toxic chemical or a 
pathogen. I think they are so different that in fact anytime 
you use an approved drug under the tensions of war with the 
possibility of bombs bursting, with personal suffering from 
lack of sleep, with the kind of situation the military are in, 
it is hardly what is conceived when a drug is carefully tested 
in a clinical trial where all of the variables in that trial 
are, so far as possible, carefully controlled.
    I was partially reassured by the answers given, especially 
by Dr. Raub, but that part of the policy needs to be further 
clarified. We must consider that whether this drug is approved 
or not, when it is being used, in battlefield conditions it 
should be treated as an off-label situation. Consistent with 
FDA practice in all other kinds of off label situations, 
careful documentation of the effects of the use of that drug 
should be collected, and I think my recommendation is 
consistent with Dr. Caplan's.
    In the intervening time since 1990 in the testing of drugs 
for civilian use, there has grown up a practice of trial 
surveillance by Data and Safety Monitoring Boards. We now have 
more than 10 years experience with such boards. Their 
functioning has been eveloving what those boards are doing is 
tracking adverse events--not simply the number of adverse 
events and the kind of adverse events--but adverse events on a 
case-by-case basis suffered by each subject of the drug trial. 
That's the kind of monitoring that I think is necessary.
    Obviously, if you get a report from a military unit that 
there were 25 or 30 adverse events ranging from temporary rash 
to persistent headache, that doesn't tell you very much about 
whether those headaches or that rash were caused by the drug. 
It also doesn't allow you any followup with the individual. 
Because although you know that those adverse events occurred in 
that unit, you don't know which event applied to which military 
personnel. If adverse event data are to be meaningful, the 
adverse events have to be tracked by statisticians who relate 
each adverse event to as individual person. Then those who 
suffer a significant number of severe adverse events an be 
followed indefinitely or perhaps as long as they live. That way 
we can really find out how good or how bad these drugs are and 
whether they will be used in the future.
    I think, furthermore, that the Data and Safety Monitoring 
Board [DSMB] would, in supplementing the work of the IRB that 
is already required, should be functioning in peacetime. The 
DSMB's ought to include about one-third military personnel, 
one-third civilian technical personnel, and one-third lay 
people, so that those boards represent the public. They should 
not be overwhelmed by military personnel, and both IRBs and 
DSMBs ought to be cleared for national security.
    One of the difficulties that we had back in 1990 was that 
we had only the military telling us in very general terms, ``we 
need approval of these drugs and we need them right away for 
the safety of our troops,'' the implication being that any 
denial of these drugs would somehow be sending our troops into 
battle without proper equipment. We had no way of independently 
evaluating that kind of information. For that reason I think 
these boards should be given security clearance to understand 
the risks, so far as they can be foreseen, that the military 
will be facing.
    And, finally, I think there must be scrutiny either by the 
IRB, by the DSMBs or some other group to make certain that the 
training information is kept up to date. When the 1990 
committee looked at the training information that was available 
on PB, we found that it was wildly inaccurate. Training manuels 
did not include the data that was known at the time. 
Consequently, military personnel who relied on the training 
data had bad information. There could have been no honest, 
informed consent because our troops didn't know the limitations 
of that drug, they did not know that it could not do all the 
things that were claimed for it in the military training 
manuals.
    So far as I know, there has not been a linkage established 
between the training manuals which virtually every potential 
combatants uses and the information that is ever changing as we 
get more information and collect more data about these drugs.
    That must be, now that we have computers and other much 
more rapid means of communication, it should be easy to keep 
data up to date within a matter of a week or two and personnel 
must be required to update their information so that they are 
and remain informed. Had I been a soldier in the Gulf war, 
basing my decisions on the training manuals, I would have felt 
that I was entirely immune to damage from chemical warfare or 
botulinum of various kinds, because the manuals overstated the 
effects of those drugs. Whereas, in fact, they can reduce those 
damaging effects, but they are far from a shield that totally 
protects one against chemical or biological weapons.
    That is the burden of my criticism. It is not that I think 
what has been proposed is not an improvement, and it is miles 
ahead of where we were in 1990. But still more needs to be 
done, and I think a lot of it can be done by clarification, 
communication and creation of DSMBs and by careful attention to 
the collection of data.
    Thank you, Mr. Chairman.
    [The prepared statement of Mr. McCarthy follows:]
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    Mr. Shays. Thank you both very much.
    This is not intended to cast aspersions on anyone, but I 
notice that Dr. Raub is here. I would like to thank you for 
staying.
    Is there anyone from DOD or from the Office of Management 
and Budget that is here representing--not to speak but someone 
who will carry on that information we heard?
    Thank you.
    Which--DOD. Thank you for being here.
    Anyone from OMB?
    I am going to print up both your responses to your--both 
your comments as the transcript will be printed, and we are 
going to send it both to DOD and OMB, because I think that your 
comments are helpful and could make the Executive order more 
effective.
    I will just comment, Dr. McCarthy, on your last point about 
if you were in the Persian Gulf. I think probably what I would 
have done is if I thought PB--a certain dosage would protect me 
at a certain level, I would have really blown it and taken 
twice as much.
    Mr. McCarthy. That is another danger by the way.
    Mr. Shays. I did that with my lawn this summer. I thought 
if a little fertilizer was good, I would use twice as much. I 
have a very dead lawn.
    Mr. McCarthy. I have destroyed some lawns myself.
    Mr. Shays. You have answered basically all the questions 
that I really intended to ask. I am just struck by some 
comments. It seems to me you need one monitoring board. It 
strikes me there needs to be some distance. I agreed with all 
four of your points, Dr. Caplan. It makes me want to write a 
letter to both OMB and to DOD to make some suggestions.
    Dr. Raub, I would love to invite you not in a way to have a 
debate but just to respond to what you heard, because I have 
really no questions I want to ask. If you don't mind, I do know 
you were here and were paying attention.
    Mr. McCarthy. Parenthetically there, I would like to say 
there was a time when Dr. Raub was my immediate supervisor. I 
have great respect for his opinions, and I don't expect that we 
are going to end up disagreeing very much.
    Mr. Shays. Does that mean that you just feel an obligation 
to agree with him?
    Mr. McCarthy. No. And he knows that even when I was his 
subordinate I did not always agree with him.
    Mr. Caplan. Mr. Chairman, I feel an obligation to clarify 
one thing that came up in the previous panel, and it does 
relate to the issues of informed consent and off label, which 
were hard to follow and were confusing.
    It is true doctors can use drugs off label. It is never 
true they can do so without the informed consent of the 
patient. It is true they have discretion to try out all things. 
You are not immunized from getting informed consent. When we 
are talking at the policy level about going off label for PB or 
tomorrow's next generation of vaccines against something, there 
will be off-label uses, doctors have discretion to use them, 
but you would still require a waiver of informed consent to do 
so. So you are not privileged to do whatever you want, as long 
as you can take something off label.
    Mr. Shays. But let me just make sure I am clear on the 
terminology now. You have to inform them, or they can, without 
a waiver, object to taking the drug?
    Mr. Caplan. Absolutely, can still object to taking the drug 
without that waiver. You could object. So the presumption is 
you absolutely have the discretion as an individual doctor to 
go off label, but you are supposed to get the consent of your 
patient sometime.
    Mr. Shays. Then it seems to me then the answer of DOD would 
have been a simple one.
    Mr. Caplan. Correct.
    Mr. Shays. That scares the hell out of me.
    Mr. Caplan. Correct.
    Mr. Shays. I wish I had known that information with the 
previous panel.
    Dr. Raub.
    Mr. Raub. Thank you, Mr. Chairman. I realize in staying I 
ran the risk of coming back to the table, but----
    Mr. Shays. You know what? Let me say this. I go out of my 
way to be very courteous the second time around, because I do 
appreciate your being here.
    Mr. Raub. I understand that from prior hearings as well, 
Mr. Chairman. I did stay because of the importance of the 
issues and my high regard for my two colleagues, here, and I 
wanted to hear what they had to say.
    The interim rule as published by the FDA also includes a 
comment period, and it includes a comment period for the very 
purpose of getting this kind of analysis and commentary about 
it.
    In my judgment, I continue to believe that the hurdles are 
indeed formidable to get any product through, to get this 
waiver, and I also believe the Commissioner of Food and Drug 
and her staff have done a superb job in putting this interim 
rule together.
    That said, I don't think they believe they are in sole 
possession of revealed truth. This comment period is serious, 
and we will take seriously comments such as these and from 
other members of the public as we seek to get this right.
    Mr. Shays. Thank you. That is very comforting. Thank you 
very much.
    Dr. Caplan, do you have any other things, words of wisdom, 
that you want to make sure you put on the record like the last 
one? Dr. McCarthy.
    Mr. McCarthy. I think--as I indicated before, I think there 
needs to be appointed in every military unit that is likely to 
receive drugs of this kind, there needs to be a person there 
with responsibility, clear responsibility, for collecting the 
data and reporting it to a DSMB.
    That person who collects also needs to be thoroughly 
familiar with everything that is known about the drug at the 
time that it is being administered, so that there will be good 
information in training manuals or other issuances by the DOD 
and perhaps FDA in conjunction with DOD, there will be someone 
at the scene to answer questions and explain to military 
personnel who are trained and accustomed to obeying orders 
without much question. We need to go an extra mile in educating 
troops with the latest and best information about both the 
strengths and the limitations of our information about the 
proposed drug.
    A major training event or training effort needs to 
accompany each of these products. The whole structure including 
IRBs, DSMBs, and data collection needs to be set up in a time 
of peace. Because I know from my 1990 experience that it was 
virtually impossible to add new structures and responsibilities 
when we were morally certain that was would start within a 
matter of weeks. No such training program could be initiated in 
that kind of timeframe.
    Mr. Shays. Do any of you know--Dr. Caplan, maybe in your 
work with the President's commission--know what drugs were 
actually requested and not given informed consent, I mean not 
given a waiver?
    Mr. Caplan. None that I know of.
    Mr. Shays. We were led to believe there were some.
    Mr. McCarthy. My recollection was, at least in the initial 
request, an off-label use for Valium was included, and there 
was another substance, the name of which I have long since 
forgotten, that was a skin cream to help prevent skin burns 
from various kinds of chemicals that might have been used or 
included in weapons.
    When FDA looked into the skin cream, it found out that 
there was very little quality control in the manufacture of it, 
and it didn't work very well even for ordinary sunburn. The DOD 
withdrew that one.
    I don't recall what happened or why Valium was withdrawn. I 
think it was because there was great concern if each soldier 
had a large packet of Valium in his pack and an attack was 
imminent, that many soldiers might take Valium and might be 
quite passive in the face of the enemy.
    So I believe those were the reasons, but I am relying on 
memory and some anecdotes, and that may or may not be accurate.
    Mr. Shays. We will note that. Very interesting.
    Mr. Caplan. I was just going to make two other comments, 
brief ones.
    One is, it does seem to me that, in trying to understand 
the question of followup and harm that may happen and tracking 
it, it is important to emphasize one other thing which did come 
up in the Advisory Committee on Gulf War Illnesses and I am not 
sure has been prepared, and that is the importance of having a 
good sample of soldiers, military personnel, reservists as well 
as active, with good health physicals before deployment. In 
other words, it is very hard without a baseline to figure out 
what happened later.
    And I am not persuaded, and I have tried to stay on top of 
this from a distance now, that the pre-deployment health 
monitoring of the military, both Reserve and Active, a sample 
of them, not everyone, but it is enough to give us that 
baseline. So when we talked about what happened and if we get a 
waiver and what are the side effects and so on, we need to have 
that baseline in place. And that has to be something that I 
hope FDA would think about.
    The other point I would make is in the world to come, not a 
pleasant one for biological warfare, I think there may be many 
reasons why we choose not to say what it is we have, antidotes 
or preventive things, we are thinking about to the other side, 
because that world I think is going to be in flux pretty fast 
in terms of genetically engineered anthrax or genetically 
engineered other viruses and bacteria that are nasty and tough 
to lay in stockpiles of things. We may not want to say much 
publicly. That leads to reasons that informed consent might not 
be sought that have nothing to do with risk-benefit but had to 
do with national security.
    In those circumstances, I hope that FDA takes seriously the 
need it is going to have to carefully assess that request 
before agents are deployed more than consultatively. It is 
going to have to make a hard call, and I hope they have the 
administrative authority to do it.
    I think my prediction, Mr. Chairman, would be in a world to 
come we are going to be playing a sort of roulette with what we 
have got and what the other side has, and requests could get 
pretty frequent, and the only stopping point for those requests 
is going to be behind the door at FDA consideration, what the 
evidence looks like. It may be the skin cream sort of thing 
that Charles is talking about, or it may be something useful. 
But you are going to need the authority to do that, and I am 
not quite convinced yet that that is laid out in the way the 
Executive order and the proposed final rule are laid out.
    Mr. Shays. This is really fascinating.
    Dr. McCarthy, any other comment you want to make?
    Dr. Raub.
    Mr. Raub. No, sir.
    Mr. McCarthy. I just want to thank the committee for giving 
us this opportunity.
    Mr. Shays. Let me just ask one other last area, and you 
triggered it, and I am not trying to prolong this hearing, but 
I just want to know if it is something I should be thinking 
more about, and that is with nuclear weapons and a missile 
delivery system, there was the debate about a missile defense 
system, and basically we allowed the Russians, the Soviet 
Union, to protect Moscow and we were allowed to protect a 
certain area, but there was the general view if we started to 
protect they would start to protect, and then there would be 
almost a willingness potentially to use the weapon thinking you 
could protect yourself.
    So what you said, Dr. Caplan, is triggering this emotion. 
If, for instance, an adversary believes they have protected 
their force against certain chemicals or biological agents, 
would they be somewhat inclined to then use them and does 
that--is the best protection, potentially, not doing the 
Russian roulette, literally saying if you use this weapon, then 
we will use all of the force necessary, even nuclear, to 
respond to weapons of mass destruction, rather than trying to 
have a prophylactic in one area or another and try to guess 
where that is going to be? Is this an issue policymakers are 
having a significant dialog about?
    Mr. Caplan. I don't think sufficiently. Because I think we 
are stuck in thinking, unfortunately, about the array of 
primitive biological weapons out there, the anthrax, which in 
some sense is more interesting as a terrorist weapon than it is 
to put on a battlefield. If you are trying to win a battle, you 
don't want someone keeling over from anthrax 30 days later. You 
want them dead relatively quickly, I would assume. So chemical 
weapons look more interesting. Biological have different 
impacts.
    I think, again, looking at the genomapping project, looking 
at what is out there for the ability to do targeted attacks on 
people with particular genotypes, this is coming. The kind of 
policy question you are asking about for dealing with both 
military situations and terrorist situations, for approval for 
preventive agents, it is going to take some rethinking of our 
policies about how we want to deal with that.
    Just having the old stocks of the old disease entities and 
the old stocks of the old chemical weapons, well, it is the 
21st century. We are about to be able to change those fast, and 
we may need to have both treaties and agreements about how this 
is going to play out and also keep something in our hip pocket 
about how we are going to respond if somebody is foolish enough 
to launch this kind of thing.
    So I would say, yes.
    Mr. Shays. I think the biggest deterrent to Saddam Hussein 
using chemical weapons was he knew that Iraq would be 
annihilated.
    Mr. Caplan. Yes. I think that kind of thinking is going to 
be important for us to continue to engage in about what our 
defense posture is going to be in the face of these things. 
Because if you can change a virus, say, smallpox, into 
something nastier, or anthrax, relatively quickly, and make it 
something you can't protect against under any circumstances, or 
targeted to particular sub-groups of a population, you are into 
an era of warfare we haven't thought through as a matter of 
political policy.
    Mr. Shays. I have concluded my questions.
    Dr. Raub, I again appreciate your making the point that 
this is an interim rule and you are listening and so are 
others. I appreciate that a lot.
    Do you have any other comment you would like to make?
    Mr. Raub. No, sir.
    Mr. Shays. Dr. McCarthy, are you all set?
    Mr. McCarthy. Yes, I am all set.
    I would like to simply comment and say, for the very 
reasons that you intimated and Dr. Caplan emphasized, I think 
the people who are reviewing these things need to have security 
clearance so that they can make those kinds of balancing 
recommendations about should we be developing these kinds of 
defenses, are they only likely to escalate or call for new 
kinds of attacks because we can now defend against this one, so 
it invites our opponents to develop another.
    I think that is a balancing kind of judgment, and I don't 
think it can be done by those who do not have security 
clearance to understand the best intelligence we have and to 
wield those judgments carefully. That is why, even though I 
would like to see a number of civilians on these committees, I 
think they have to have clearance. Otherwise, they are flying 
blind.
    Mr. Shays. I totally agree with that. I agree with most of 
the other comments made by this panel. Thank you very much.
    We will conclude this hearing. Thank you.
    [Whereupon, at 12 noon, the subcommittee was adjourned.]

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