U.S. GOVERNMENT PRINTING OFFICE

64–776 CC WASHINGTON : 2000

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

(II)

COMMITTEE ON GOVERNMENT REFORM

DAN BURTON, Indiana, Chairman

BENJAMIN A. GILMAN, New York

CONSTANCE A. MORELLA, Maryland

CHRISTOPHER SHAYS, Connecticut

ILEANA ROS-LEHTINEN, Florida

JOHN M. MCHUGH, New York

STEPHEN HORN, California

JOHN L. MICA, Florida

THOMAS M. DAVIS, Virginia

DAVID M. MCINTOSH, Indiana

MARK E. SOUDER, Indiana

JOE SCARBOROUGH, Florida

STEVEN C. LATOURETTE, Ohio

MARSHALL ‘‘MARK’’ SANFORD, South

Carolina

BOB BARR, Georgia

DAN MILLER, Florida

ASA HUTCHINSON, Arkansas

LEE TERRY, Nebraska

JUDY BIGGERT, Illinois

GREG WALDEN, Oregon

DOUG OSE, California

PAUL RYAN, Wisconsin

HELEN CHENOWETH-HAGE, Idaho

DAVID VITTER, Louisiana

HENRY A. WAXMAN, California

TOM LANTOS, California

ROBERT E. WISE, JR., West Virginia

MAJOR R. OWENS, New York

EDOLPHUS TOWNS, New York

PAUL E. KANJORSKI, Pennsylvania

PATSY T. MINK, Hawaii

CAROLYN B. MALONEY, New York

ELEANOR HOLMES NORTON, Washington,

DC

CHAKA FATTAH, Pennsylvania

ELIJAH E. CUMMINGS, Maryland

DENNIS J. KUCINICH, Ohio

ROD R. BLAGOJEVICH, Illinois

DANNY K. DAVIS, Illinois

JOHN F. TIERNEY, Massachusetts

JIM TURNER, Texas

THOMAS H. ALLEN, Maine

HAROLD E. FORD, JR., Tennessee

JANICE D. SCHAKOWSKY, Illinois

———

BERNARD SANDERS, Vermont

(Independent)

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

ILEANA ROS-LEHTINEN, Florida

JOHN M. MCHUGH, New York

JOHN L. MICA, Florida

DAVID M. MCINTOSH, Indiana

MARSHALL ‘‘MARK’’ SANFORD, South

Carolina

LEE TERRY, Nebraska

JUDY BIGGERT, Illinois

HELEN CHENOWETH-HAGE, Idaho

ROD R. BLAGOJEVICH, Illinois

TOM LANTOS, California

ROBERT E. WISE, JR., West Virginia

JOHN F. TIERNEY, Massachusetts

THOMAS H. ALLEN, Maine

EDOLPHUS TOWNS, New York

BERNARD SANDERS, Vermont

(Independent)

JANICE D. SCHAKOWSKY, Illinois

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

(III)

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

(1)

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 informaVerDate 11-MAY-2000 07:49 Aug 24, 2000 Jkt 000000 PO 00000 Frm 00005 Fmt 6633 Sfmt 6633 C:\DOCS\64776.TXT HGOVREF1 PsN: HGOVREF1
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tion 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:]

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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 PresiVerDate 11-MAY-2000 07:49 Aug 24, 2000 Jkt 000000 PO 00000 Frm 00008 Fmt 6633 Sfmt 6633 C:\DOCS\64776.TXT HGOVREF1 PsN: HGOVREF1
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dent 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 wellbeing 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.

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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 needVerDate 11-MAY-2000 07:49 Aug 24, 2000 Jkt 000000 PO 00000 Frm 00025 Fmt 6633 Sfmt 6633 C:\DOCS\64776.TXT HGOVREF1 PsN: HGOVREF1
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ed 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.

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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.

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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.

45

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.

46

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

47

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

48

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.

49

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.

50

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

51

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

52

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.

53

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

54

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.

55

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?

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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.

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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 tickborne 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.

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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.

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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, InstituVerDate 11-MAY-2000 07:49 Aug 24, 2000 Jkt 000000 PO 00000 Frm 00063 Fmt 6633 Sfmt 6633 C:\DOCS\64776.TXT HGOVREF1 PsN: HGOVREF1
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tional 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

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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

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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

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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 preVerDate 11-MAY-2000 07:49 Aug 24, 2000 Jkt 000000 PO 00000 Frm 00087 Fmt 6633 Sfmt 6633 C:\DOCS\64776.TXT HGOVREF1 PsN: HGOVREF1
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ventive 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 relVerDate 11-MAY-2000 07:49 Aug 24, 2000 Jkt 000000 PO 00000 Frm 00088 Fmt 6633 Sfmt 6633 C:\DOCS\64776.TXT HGOVREF1 PsN: HGOVREF1
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atively 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.

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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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