40996 Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Proposed Rules

ADDRESSES: Secretary to the Board,

Railroad Retirement Board, 844 North

Rush Street, Chicago, Illinois 60611.

FOR FURTHER INFORMATION CONTACT:

Thomas W. Sadler, Senior Attorney,

Railroad Retirement Board, 844 North

Rush Street, Chicago, Illinois 60611,

telephone (312) 751–4513, TTD (312)

751–4701.

SUPPLEMENTARY INFORMATION: Part 295

describes the Board’s requirements for

obtaining an enforceable order directing

the Board to partition a railroad

retirement annuity incident to a divorce,

settlement, or annulment. Section

295.1(b) describes what benefits are

subject to division under this part.

Section 295.5(e)(1) further defines the

net amount of benefits subject to

division as excluding amounts deducted

for an employee’s elected Medicare Part

B premium. When § 295.5(e)(1) was

initially approved in 1986, the Board

was concerned about the risk that

Medicare premium deductions might

not be satisfied from the nondivisible

portion of an employee’s annuity in the

event that the portion would not be

payable due to work deductions. In

practice, however, the agency has

determined that only in rare cases is the

nondivisible portion insufficient to

accommodate the Medicare Part B

deduction. The Medicare Part B

premium is a personal expense elected

to be made by the employee. The Board

believes that it is more consistent with

the nature of the Part B premium that it

be paid entirely by the employee rather

than, in effect, partly by the employee

and partly by the divorced spouse.

Accordingly, the agency proposes that

the Medicare Part B deduction need not

be deducted from the divisible benefits

prior to partition in an action for

divorce, settlement, or annulment.

The Board, with the concurrence of

the Office of Management and Budget,

has determined that this is not a

significant regulatory action under

Executive Order 12866; therefore, no

regulatory impact analysis is required.

There are no information collections

associated with this rule.

List of Subjects in 20 CFR Part 295

Railroad employees, Railroad

retirement.

For the reasons set out in the

preamble, chapter II of title 20 of the

Code of Federal Regulations is proposed

to be amended as follows:

PART 295—PAYMENTS PURSUANT

TO COURT DECREE OR COURTAPPROVED PROPERTY SETTLEMENT

1. The authority for part 295

continues to read as follows:

Authority: 45 U.S.C. 231f; 45 U.S.C. 231m.

§ 295.5 [Amended]

2. Section 295.5(e)(1) is amended by

removing the comma after ‘‘Board’’ and

by removing ‘‘and the amount of any

Medicare Part B premium’’.

Dated: July 24, 1997.

By authority of the Board.

Beatrice Ezerski,

Secretary to the Board.

[FR Doc. 97–20206 Filed 7–30–97; 8:45 am]

BILLING CODE 7905–01–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 50

[Docket No. 90N–0302]

Accessibility to New Drugs for Use in

Military and Civilian Exigencies When

Traditional Human Efficacy Studies

Are Not Feasible; Determination Under

the Interim Rule That Informed

Consent Is Not Feasible for Military

Exigencies; Request for Comments

AGENCY: Food and Drug Administration,

HHS.

ACTION: Request for comments.

SUMMARY: The Food and Drug

Administration (FDA) is requesting

written comments related to the

advisability of revoking or amending the

interim final rule that permitted the

Commissioner of Food and Drugs (the

Commissioner) to determine that

obtaining informed consent from

military personnel for the use of an

investigational drug or biologic is not

feasible in certain situations related to

military combat. The agency is also

soliciting written comments identifying

the evidence needed to demonstrate

safety and effectiveness for such

investigational drugs that cannot

ethically be tested on humans for

purposes of determining their efficacy.

FDA is seeking written comments from

all interested parties, including, but not

limited to: Consumers, patient groups,

veterans and veteran groups, active-duty

military personnel, organizations and

departments, ethicists, scientists,

researchers with particular expertise in

this area, and health care professionals.

The written comments are intended to

provide FDA with information to help

the agency in making policy decisions

on the use of investigational products

during military exigencies and the

appropriate evidence needed to

demonstrate safety and effectiveness for

drug and biological products used in

military or other exigencies when

traditional human efficacy studies are

not feasible.

DATES: Submit written comments by

October 29, 1997.

ADDRESSES: Submit written comments

on the questions identified in section II

of this document (specifically

referencing the number of the

question(s) being addressed) to the

Dockets Management Branch (HFA–

305), Food and Drug Administration,

12420 Parklawn Dr., rm. 1–23,

Rockville, MD 20857. Two copies of any

comments are to be submitted, except

that individuals may submit one copy.

Comments are to be identified with

docket number found in brackets in the

heading of this document.

FOR FURTHER INFORMATION CONTACT:

Bonnie M. Lee, Office of the Executive

Secretariat (HF–40), Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857, 301–827–4450.

SUPPLEMENTARY INFORMATION:

I. Background

There will continue to be military

combat situations in which there will be

a threat to U.S. military personnel from

the possible use of chemical and

biological weapons. The Department of

Defense (DOD), therefore, has a

legitimate interest in protecting military

personnel by using products which may

provide protection from such chemical

and biological agents. In order to

support this interest of DOD, FDA

issued an interim rule during the

Persian Gulf War that permitted DOD to

use specified investigational products

intended to provide potential protection

against chemical and biological warfare

agents without obtaining informed

consent. A copy of the interim rule that

published in the Federal Register of

December 21, 1990 (55 FR 52813), can

be viewed on FDA’s website at http://

www.fda.gov.

Specifically, following a request from

the DOD, FDA granted waivers from its

informed consent requirements for the

use of two products in specific protocols

in the Persian Gulf War: Pyridostigmine

bromide and botulinum toxoid vaccine.

FDA recognizes that the interim final

rule did not work the way that the

agency anticipated it would work;

therefore, the agency is seeking broad

public input to provide information to

help FDA in making policy decisions on

the future use of such investigational

products and possible efficacy

demonstrations for these products.

In order to provide a context for the

decisionmaking process on the use of

pyridostigmine bromide and the
Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Proposed Rules 40997

botulinum toxoid vaccine during the

Persian Gulf War, the following

information is provided.

A. The Regulatory Process

FDA regulates the use of

investigational drugs under provisions

of the Federal Food, Drug, and Cosmetic

Act (the act). In FDA terms, drugs not

approved for marketing and drugs

studied for treatment other than that

identified in the approved labeling, are

investigational. In order for clinical

testing to proceed with unapproved

products (or, in some cases, for testing

approved products for unapproved

uses), an investigational new drug (IND)

application is filed with FDA. The IND

must contain information sufficient to

demonstrate that it is reasonable to

study the drug in humans, including

drug composition, manufacturing and

control data, the results of animal

studies and, if available, prior human

testing, and the protocol for the planned

study. The investigator must agree to a

number of commitments including

obtaining approval of an institutional

review board (IRB) before proceeding,

obtaining written informed consent

from subjects, and reporting adverse

effects that occur as specified in the

protocol.

The act requires that investigators

inform subjects receiving drugs under

an IND that the drugs are investigational

and ‘‘obtain the consent of such human

beings or their representatives, except

where they deem it not feasible, or in

their professional judgment, contrary to

the best interests of such human

beings.’’ There have been few instances

in which obtaining informed consent

has not been considered feasible or

contrary to patients’ interests.

During the months preceding the

Persian Gulf War, DOD had discussions

with FDA regarding the potential use of

specific investigational products in

military personnel serving in the Gulf.

It was thought that the products

discussed represented the best

preventive or therapeutic treatment for

diseases endemic to the area and in

providing protection against possible

chemical or biological weapons. DOD

requested the assistance of FDA in

allowing the use of these products in

certain battlefield or combat-related

situations in which they considered

obtaining informed consent ‘‘not

feasible.’’ DOD’s explanation as to why

obtaining informed consent would not

be feasible under battlefield conditions

included the following:

(1) It is not acceptable from a military

standpoint to defer to whatever might be

the soldier’s personal preference

concerning a preventive or therapeutic

treatment that might save his life, avoid

endangerment of the other personnel in

his unit and accomplish the combat

mission.

(2) Based on unalterable requirements

of the military field commander, it is

not an option to excuse a nonconsenting

soldier from the military mission.

(3) It would not be defensible

militarily, or ethically, to send the

soldier unprotected into danger.

(4) Special military exigencies

sometimes must supersede normal

rights and procedures that apply in the

civilian community and, thus, military

regulations state that military members

may be required to submit to medical

care determined necessary to preserve

life, alleviate suffering or protect the

health of others.

At the time, FDA gave considerable

deference to the DOD’s judgment and

expertise regarding the feasibility of

obtaining informed consent under

battlefield conditions. Thus, in response

to DOD’s request, in the Federal

Register of December 21, 1990 (55 FR

52813), FDA published an interim

regulation amending its informed

consent regulations at 21 CFR 50.23(d).

B. The Interim Regulation

The interim regulation allowed the

Commissioner to determine, upon

receipt of an appropriate request from

DOD, that obtaining informed consent

from military personnel for use of a

specific investigational drug or biologic

would not be feasible in certain

circumstances, and to grant a waiver

from the requirement for obtaining such

consent.

The exception applied, on a case-bycase basis, only to investigational drugs

(including antibiotic and biological

products) for use in a specific military

operation involving combat or the

immediate threat of combat. The

regulation requires the request to

include: (1) The justification for the

conclusion (made by physicians

responsible for the medical care of the

military personnel involved and the

investigators involved) that the use is

required to facilitate the

accomplishment of the military mission,

and the use would preserve the health

of the individuals and the safety of other

personnel, without regard for any

individual’s preference for alternate

treatment or no treatment; and (2) a

statement that a duly constituted IRB

has reviewed and approved the use of

the investigational drug without

informed consent.

Under the interim rule, the

Commissioner may find that informed

consent is not feasible (and thus may be

waived) ‘‘only when withholding

treatment would be contrary to the best

interests of military personnel and there

is no available satisfactory alternative

therapy.’’ The rule sets forth four

additional factors that the

Commissioner is to consider in making

his determination. These factors are: (1)

The extent and strength of the evidence

of the safety and efficacy of the drug for

the intended use, (2) the context in

which the drug will be administered

(e.g., battlefield or hospital), (3) the

nature of the disease or condition for

which the preventive or therapeutic

treatment is intended, and (4) the nature

of the information to be provided to the

recipients of the drug concerning the

potential risks and benefits of taking or

not taking the drug. A determination by

the Commissioner that obtaining

informed consent is not feasible and

withholding treatment would be

contrary to the best interests of military

personnel expires at the end of 1 year,

unless renewed at DOD’s request, or

when DOD informs the Commissioner

that the specific military operation

creating the need for the use of the

investigational drug has ended,

whichever is earlier. In addition, when

the Commissioner has issued a waiver

to DOD, he may revoke the waiver based

on changed circumstances.

The appropriate FDA review division

and the Informed Consent Waiver

Review Group (ICWRG) assessed each

request for waiver from the informed

consent requirements. The ICWRG

included senior management of FDA

and the National Institutes of Health’s

Office of Protection from Research

Risks, supplemented by technical

agency experts as appropriate for the

particular investigational drug being

considered for exception. The ICWRG

considered DOD’s justification

supporting the request for the waiver

and the reviewing division’s evaluation

of the available safety and efficacy data.

The ICWRG requested additional

supporting information in some cases

and identified changes needed in the

information to be provided to the

troops. The ICWRG then made a

recommendation to the Commissioner

regarding whether or not to grant the

waiver. The Commissioner made a

decision on the request and informed

DOD in writing.

On December 28, 1990, DOD

submitted protocols under IND’s and

requests for waiver of informed consent

for pyridostigmine bromide 30-

milligram (mg) tablets and botulinum

toxoid vaccine. (Subsequently, DOD

submitted a waiver request for

multishield topical skin protectant, but

later withdrew this request.)

Pyridostigmine bromide was considered
40998 Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Proposed Rules

a potentially useful pretreatment against

certain nerve gases; botulinum toxoid

vaccine is widely accepted as offering

protection against toxins produced by

Clostridium Botulinum, the bacterium

that causes botulism.

The Commissioner approved DOD’s

waiver requests for pyridostigmine

bromide 30-mg tablets and botulinum

toxoid vaccine on December 31, 1990,

and January 8, 1991, respectively. Both

products were administered to portions

of the military personnel who

participated in Operation Desert Storm.

Following the cessation of combat

activities, the Assistant Secretary of

Defense (Health Affairs) notified the

Commissioner in a letter dated March

15, 1991, that DOD considered the two

waivers granted under the interim rule

to be no longer in effect. He also

informed the Commissioner that DOD

had ultimately decided to administer

the botulinum toxoid on a voluntary

basis.

C. Comments Received on the Interim

Rule

Twenty-two written comments were

submitted to the agency in the brief 30-

day comment period following

publication of the interim rule in the

Federal Register of December 21, 1990.

Comments were received from

physicians, members of IRB’s,

organizations concerned with bioethical

issues, patient advocacy groups, and

private citizens. The majority of the

comments were supportive of the rule,

although often with some qualification

or suggested change. However, a

number of comments expressed

vehement opposition to the interim rule,

both on general principle and with

regard to one or more of its provisions.

For example, one comment stated that

the request for waiver of informed

consent is merely an expedient solution

to a problem that should be solved

much better in other ways. This

comment suggested that FDA modify its

drug approval process so that therapies

such as those that were sanctioned for

use under the interim rule could be

granted marketing approval

notwithstanding the absence of

substantial evidence of their

effectiveness against nerve gas or

biological warfare agents. Several

comments stated that the interim

regulation did not provide for recipients

of investigational therapies to receive

appropriate information on the

treatment to be administered. Two

comments stated that the interim rule

should be modified to require that the

reviewing IRB be unaffiliated with DOD.

Five comments stated that the interim

rule is a violation of fundamental

ethical principles. The comments

described the rule as ‘‘* * * a flagrantly

immoral violation of human rights,’’

adding that ‘‘Wartime does not justify

experimentation without consent,’’ and

‘‘No explanation, whatever it might be,

is acceptable to justify these actions.’’

D. Summary of Litigation Regarding the

Interim Rule

On January 11, 1991, Public Citizen

Health Research Group filed suit against

the Department of Health and Human

Services in the United States District

Court on behalf of an unnamed

serviceman stationed in Saudi Arabia,

his wife, and all others similarly

situated. In the Complaint, the plaintiff

(‘‘Doe’’) alleged that: (1) The interim

rule was outside FDA’s statutory

authority under the act, (2) DOD’s use

of unapproved investigational drugs,

under the informed consent waiver,

could not be reconciled with language

in the 1985 Defense Department

Authorization Act, and (3) the

Government’s use of drugs on

unconsenting persons was a deprivation

of liberty in violation of the Fifth

Amendment. The district court

dismissed the Complaint holding that

the Complaint questioned ‘‘a military

decision that is not subject to judicial

review.’’ (Doe v. Sullivan, 756 F. Supp.

12, 14 (D.D.C. 1991)). In an alternative

holding, the district court also rejected

on the merits the statutory and

constitutional challenges stated in the

complaint.

On appeal, a three-judge panel of the

United States Court of Appeals for the

District of Columbia Circuit affirmed by

a two-to-one vote the district court’s

order dismissing the Complaint on the

grounds that FDA’s rule was within

FDA’s authority, and not barred by the

1985 Department of Defense

Authorization Act or the due process

clause of the Fifth Amendment. The

dissenting judge was of the opinion that

the case was moot.

E. DOD’s Experience With

Pyridostigmine Bromide and Botulinum

Toxoid

Following the approval of the waiver

requests, DOD dispensed

pyridostigmine bromide tablets and

administered botulinumtoxoid to U.S.

troops involved in Operations Desert

Shield and Desert Storm who were

deemed to be at high risk for exposure

to organophosphorus nerve agents or

bacterial agents. As part of the legal

requirements for the use of products

under an IND, DOD was required to

collect data on the safety and efficacy of

the two agents. This information is

summarized as follows:

1. Safety Data on Pyridostigmine

U.S. troops who were deemed to be at

high risk for exposure to

organophosphorus nerve agents

received pyridostigmine bromide tablet

packages for self-administration use

when ordered to take them as

prophylaxis against nerve agents. Unit

commanders had discretion on whether,

and when, to order use of the

pyridostigmine bromide, and could

delegate this authority to the lowest

level of field command. Documentation

does not exist on how far down the

command chain the authority was

delegated in each unit, or whether or

when each unit issued orders to begin

taking the pyridostigmine, or who took

pyridostigmine.

The Department of the Army

conducted three separate surveys in an

effort to determine the incidence and

severity of side effects associated with

the use of pyridostigmine bromide as a

nerve agent pretreatment.

Survey I was a questionnaire sent to

42 selected medical personnel involved

in Operation Desert Shield and

Operation Desert Storm; 23 of these

questionnaires were completed and

returned. Among the 23 medical officers

who returned the survey, 10 responded

that their overall impression was that

the drug was tolerated either very well

or well. The most common side effects

reported were gastrointestinal

(abdominal cramps, nausea, and

diarrhea). Less common side effects

were weakness and light-headedness,

exacerbation of asthmatic symptoms,

fatigue, sleep disturbances, and reduced

mental concentration. Of the 5,825

medical personnel reported on, 8 were

hospitalized for side effects that were

attributed to pyridostigmine. The

reasons listed for hospitalization

included exacerbation of cholelithiasis,

asthma, and allergic skin reaction.

Survey II was a questionnaire given to

an unspecified number of soldiers

deployed in Operation Desert Storm;

149 of these soldiers responded. Of

those individuals who took the drug,

37.5 percent experienced side effects.

The most common side effects were

gastrointestinal in nature. Nausea was

reported most frequently (11 percent of

subjects), and headache was the second

most frequent side effect reported (7.5

percent of subjects).

Survey III was designed to document

the effects of pyridostigmine on

aviators’ ability to carry out combat

missions. One hundred eighteen

aviators participated in the survey, 48 of

whom were taking other medications

concomitantly. The majority of those

taking other medications were taking
Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Proposed Rules 40999

the antibiotic ciprofloxacin. Twenty-six

of the 108 aviators who indicated that

they had taken the drug reported

experiencing side effects they attributed

to pyridostigmine, mainly headaches

and diarrhea.

The Journal of the American Medical

Association published the result of one

retrospective study that reported on the

18th Airborne Corps (Corps) use of

pyridostigmine. The Corps instructed

41,650 soldiers (6.5 percent women) to

take pyridostigmine at the beginning of

Operation Desert storm in January 1991.

Approximately 30 medical officers

(physicians and physician’s assistants)

provided their impressions of the

incidence of physiologic responses and

potential adverse effects to

pyridostigmine. A total of 483 aid

station or clinic visits were related to

pyridostigmine administration; 313 of

these visits were due to ‘‘gastrointestinal

disturbances severe enough to prompt

medical attention.’’ And ‘‘[a]nother 150

soldiers had frequency or urgency of

urination.’’ Less than 5 percent of the

41,650 soldiers complained of

headaches, rhinorrhea, diaphoresis, or

tingling of extremities. The article

reported that 1 percent of the troops

perceived the need for a medical visit

and less than 0.1 percent discontinued

pyridostigmine based on medical advice

(LTC Jill R. Keeler, et al.,

‘‘Pyridostigmine Used as a Nerve Agent

Pretreatment Under Wartime

Conditions,’’ Journal of the American

Medical Association, vol. 266, no. 5,

August 7, 1991).

2. Safety and Efficacy Data on

Botulinum Toxoid Vaccine

As noted previously, DOD advised

FDA that the military command in the

theater of operations administered this

vaccine on a voluntary basis.

Approximately 8,000 service members

were reported to have received the

botulinum toxoid vaccine. Most of these

individuals received two doses.

The Department of the Army collected

safety information through a

retrospective survey on local and

generalized reactions experienced by

soldiers vaccinated with the botulinum

toxoid vaccine. The survey, conducted

on August 27, 1991, was given to

individuals who received one or more

doses of the vaccine (between January 3,

1991, and March 2, 1991) in the Persian

Gulf, and who had received no other

vaccines against biological warfare

agents. One hundred and twenty-one

responses were received. With respect

to local reactions, 84 percent of

vaccinated individuals reported either

no local reactions (72.5 percent) or

redness and/or swelling less than 6

inches in any dimension (11.57

percent). One individual reported postvaccination injection site pain that

temporarily (one half day) interfered

with his ability to perform his duties but

resolved quickly. With respect to

systemic reactions to the vaccine, 97.52

percent of respondents reported having

none. Of the three respondents who

reported systemic reactions, two

reported mild systemic effects such as

headache and muscle aches, and the

third also reported nausea, fever, and

fatigue; none of these events were

reported to have persisted or have

resulted in limitations on activity.

In 1992, DOD carried out a followup

study, with informed consent, on 327

selected military personnel who

received the botulinum toxoid vaccine

during Operation Desert Shield and

Operation Desert Storm. The objectives

of this study were, in part, to evaluate

the persistence of antibodies to

botulinum toxoid vaccine received

during the Gulf War and, to determine

the serological response 30 days after a

booster dose. The evaluation

demonstrated that 35 of the 327 had

measurable antibody 18 to 24 months

following primary vaccination. The

percentage of antibody varied

depending on whether the individuals

had received 1, 2, or 3 primary

vaccinations ((0/10 (0 percent), 27/244

(11.1 percent), and 8/73 (11 percent) of

individuals who had received 1, 2, or 3

primary vaccinations, respectively).

This response was to be expected at this

followup time point in individuals

receiving anything less than the full

primary immunization and booster

dose. Thirty days after the booster dose

was administered, 7/10 (70 percent),

238/244 (97.5 percent), and 72/72 (98.6

percent) of individuals who had

received 1, 2, or 3 of the primary dose

series, respectively, responded with a

significant increase in toxin neutralizing

antibody titer to botulinum type A.

3. Information Supplied to Military

Personnel

DOD has stated that its

implementation of plans for providing

service members with information about

the investigational products was

frustrated due to time limitations.

In order to evaluate the effectiveness

of its efforts to disseminate information

to military personnel regarding the

safety, risks, and possible benefits of

pyridostigmine, the Army surveyed an

unspecified number of personnel

regarding their views on the adequacy of

the information that they received. This

was a part of Survey II described in

section I.E.1 of this document. Those

surveyed were asked whether they

thought the training that they received

was adequate and to comment about any

problems with their training.

One hundred forty-nine individuals

responded to this survey. In response to

the question ‘‘Was training about

pyridostigmine adequate?’’, 43.7 percent

of the respondents answered in the

negative. Most of those who felt that the

training was inadequate expressed a

desire for more information on side

effects, long-term effects, and the drug’s

mechanism of action. The following is

a sample of some of the comments

received (both by those who felt the

training was inadequate and those who

felt it was adequate but could have been

better):

(a) ‘‘No standard side effects given.’’

(b) ‘‘No training on side effects.’’

(c) ‘‘People were worried about the

drug’s side effects. Many people

avoided taking it. Some people would

double dose after missing one.’’

(d) ‘‘Not trained on drug action, but

yes on side effects.’’

(e) ‘‘Combat lifesavers brief it and said

it was FDA approved.’’

(f) ‘‘Many soldiers didn’t take the

tablets due to the fact that they weren’t

FDA approved or thought not.’’

(g) ‘‘Didn’t know what it did, what it

was for. Disregarded instructions to take

it.’’

(h) ‘‘Training was not enough in

layman’s terms. You would need to

know more about nerve agents.’’

Veterans made similar comments on

the adequacy of the information they

received at hearings before the Senate

Committee on Veterans’ Affairs and the

Presidential Advisory Committee on

Gulf War Veterans’ Illnesses.

As part of Survey I described in

section I.E.1 of this document, 15 of the

23 medical officers who returned the

survey responded that to their

knowledge, the information sheet on

pyridostigmine bromide was not

distributed to personnel instructed to

take pyridostigmine bromide. Two

respondents said that the information

was distributed, and one respondent,

whose unit was not instructed to begin

pretreatment with pyridostigmine

bromide, replied that he had the sheet

available for distribution.

Although FDA did not require the

Army to attempt to evaluate the

effectiveness of its educational efforts,

the Army did so in an effort to monitor

its own performance and perhaps learn

about how education might be improved

in the future. While it is difficult to

evaluate the validity of the Army’s

findings (due to the difficulty of

measuring the effect of response bias in

Survey II), FDA is concerned about the

high level of dissatisfaction expressed
41000 Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Proposed Rules

by this small sample of military

personnel. Their responses indicate that

the information on pyridostigmine was

not distributed as intended and the

Army’s educational activities were

uneven and possibly inappropriate to

the education level of all personnel.

Their responses also indicate that

because of the inadequate information

provided to the soldiers, that at least

some soldiers either took the wrong

amount of pyridostigmine or

disregarded orders to take it completely.

Based on subsequent DOD statements,

FDA has concluded that the information

sheet on pyridostigmine was not

provided and disseminated to military

personnel in the Gulf as conditioned in

the Commissioner’s letter granting the

waiver under the interim rule.

With respect to botulinum toxoid

vaccine, there is a lack of clarity as to

whether the conditions of waiver were

met and applied or whether informed

consent was actually obtained.

F. Other Information Related to the

Interim Rule

There has been extensive examination

of the use of the interim rule,

pyridostigmine bromide, and the

botulinum toxoid vaccine during

Operation Desert Storm. This focused

examination is, in part, the result of

interest in determining the cause of a

variety of health effects suffered by

veterans who served in the Gulf War.

On May 6, 1994, the United States

Senate Committee on Veterans’ Affairs

held a hearing on ‘‘Is Military Research

Hazardous to Veterans’ Health? Lessons

From World War II, the Persian Gulf,

and Today.’’ The Chairman, in his

opening statement, stated his view that

the issue needed to be resolved.

Witnesses at the hearing included

ethicists, four veterans with stories of

illnesses allegedly related to exposures

they experienced either in the military

or working for the military, and

scientists and officials from the

Department of Veterans Affairs, DOD,

FDA, and the Department of

Agriculture.

The Presidential Advisory Committee

on Gulf War Veterans’ Illnesses’ final

report reviewed these issues

extensively. In its interim report

(February 1996), the committee

described a number of shortcomings in

DOD’s use of investigational products

during the Gulf War and recommended,

among other things, that:

If FDA decides to reissue the interim final

rule as final, it should first issue a Notice of

Proposed Rule Making. Among the areas that

specifically should be revisited are: adequacy

of disclosure to service personnel; adequacy

of recordkeeping; long term followup of

individuals who receive investigational

products; review by an IRB outside of DOD;

and additional procedures to enhance

understanding, oversight, and accountability.

(p. 24)

This report further stated:

The activities of FDA and DOD related to

the use of drugs and biologics intended to

protect against [chemical and biological

warfare] CBW remain an area of considerable

interest to the Committee. In particular, we

plan to explore with FDA possible

alternatives to the interim final rule to help

ensure troops are protected against CBW.

Some observers have suggested an approval

standard that recognizes surrogate endpoints

and other data indicative of efficacy for

vaccines, drugs, devices, and antibiotics

intended for CBW defense might be a more

appropriate policy than a waiver of informed

consent. (p. 44)

On May 7, 1996, Public Citizen, the

National Veterans Legal Services

Program, and the National Gulf War

Resource Center, Inc., submitted a

petition to FDA requesting that the

Commissioner repeal the interim rule.

The petition set forth a number of

grounds for this request, including: The

ethics of the rule continues to be

questioned; the military did not provide

the information regarding the effects of

experimental drugs that FDA considered

essential to permitting their use without

informed consent; DOD failed to keep

the necessary records on the

administration and effects of the

experimental drugs; the waiver of

informed consent was not necessary

(botulinum toxoid vaccine was ordered

to be given on a voluntary basis and

‘‘the fact that the PB tablets were selfadministered by the troops underscores

that it was possible to inform and obtain

the consent of the military personnel

who took these tablets’’); the safety of

the experimental drugs is still

questionable; and administration of

these drugs without informed consent

was not limited to military personnel.

The petition concluded with the

following:

The FDA should repeal the Interim Rule in

light of all the problems encountered in its

implementation. Not only did the Interim

Rule fail to operate in the manner the FDA

intended, but it also allowed the military to

circumvent the safeguards the FDA offered to

rationalize this departure from its ordinary

rules on informed consent. The military did

not follow through with many conditions

that the FDA deemed crucial to granting a

waiver of this critical requirement. (p. 26)

On September 13, 1996, the Assistant

Secretary of Defense, Health Affairs,

provided DOD’s comments on the

petition to FDA and urged that it be

denied. DOD’s comments included the

following statements:

1. When the President commits U.S.

military forces to a combat, peacekeeping, or

humanitarian deployment, the U.S.

Government has a duty to take all reasonable

precautions to bring about a successful

completion of the mission and a safe return

of the deployed forces.

2. The Government’s duty to take all

reasonable precautions to preserve the

fighting force must include recognition of the

startling proliferation of chemical and

biological weapons among potential

adversaries and terrorist organizations and an

obligation to implement the best possible

medical countermeasures.

3. Implementation of the best possible

medical countermeasures may require the

standardized treatment use of an

investigational new drug or vaccine for all

personnel at risk in a military combat

exigency, including those personnel who, for

whatever reason or no reason at all, would

prefer an alternate treatment or no treatment.

4. The current rule is an extremely limited

authority, requiring case-by-case justification,

available only under extraordinary

circumstances, and explicitly restricted to

advancing the best interests of the military

personnel concerned.

5. The current rule is fully consistent with

law and ethics.

6. Overall, notwithstanding some problems

in carrying out the designed treatment

protocols, the two uses made of the current

rule during the Persian Gulf War support the

rule’s continuation.

7. Initiatives since the Gulf War, including

current operations in Bosnia, have improved

DOD’s ability to implement medical

countermeasures under the authority of the

current rule, should that become necessary in

the future.

This petition is pending before the

agency.

II. Scope of Comments Requested

In light of the many complex ethical,

scientific, and public health issues

associated with the use of

investigational products during the Gulf

War and the waiver of the requirement

to obtain informed consent, FDA is

soliciting broad public comment on the

advisability of the agency: (1) Revoking

or amending the interim final rule that

permits the Commissioner to determine

that obtaining informed consent from

military personnel for the use of an

investigational drug or biologic is not

feasible in certain situations related to

military combat, and (2) identifying the

evidence needed to demonstrate safety

and effectiveness for such

investigational drugs that cannot

ethically be tested on humans for

purposes of determining their efficacy

because they would involve

administering a severely toxic substance

to human volunteers. The agency

encourages written comments from all

interested parties, including, but not

limited to, consumers, patient groups,

veterans and veteran groups, active

military personnel, organizations and

departments, ethicists, scientists,
Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Proposed Rules 41001

researchers with particular expertise in

this area, and health care professionals.

Interested persons may, on or before

October 29, 1997, submit to the Dockets

Management Branch (address above)

written comments regarding the

questions identified in section II of this

document (referencing the number of

the question(s) being addressed). Two

copies of any comments are to be

submitted, except that individuals may

submit one copy. Comments are to be

identified with the docket number

found in brackets in the heading of this

document. Received comments may be

seen in the office above between 9 a.m.

and 4 p.m., Monday through Friday.

The agency specifically requests

comments on the following:

A. The Interim Rule

(1) Should the agency revoke the

interim rule? If so, why?

(2) Are there circumstances under

which use of the interim rule would be

justified? If so, what are those

circumstances?

(3) The interim rule is based on the

premise that informed consent is not

feasible in military combat exigencies

because if a soldier were permitted to

say ‘‘no,’’ this could jeopardize the

individual soldier’s life, endanger other

personnel in his or her unit, and

jeopardize the accomplishment of the

combat mission. DOD has alleged that it

is not an option to excuse a

nonconsenting soldier from a military

mission. Given the experience in the

Gulf War, does this rationale still hold?

(4) Instead of waiving the requirement

for informed consent, is it feasible to

obtain anticipatory consent from

military personnel during peace time for

the future use of investigational

products during a military conflict? If it

is feasible, would such consent be valid

as ‘‘informed consent’’? What would be

the needed consent algorithm to make it

valid and feasible?

(5) Instead of waiving the requirement

for informed consent, is it feasible to

obtain anticipatory consent from

military recruits (prior to their

recruitment into the military) for the

future use of investigational products

during a military conflict? If it is

feasible, would such consent be valid?

What would be the needed consent

algorithm to make it valid and feasible?

(6) If the interim rule is needed, are

there changes that should be made to it

based on experiences during and

following the Gulf War? If so, what are

these changes and why should they be

made?

(7) Can or should the interim rule be

narrowed in scope? If so, how?

(8) If the rule were to be reproposed:

(a) Should there be a requirement that

DOD’s proposed use of the

investigational product(s) be approved

by an IRB that is independent of DOD?

If so, why should DOD be held to a

requirement not imposed on other

institutions, and what should be the

requirement for that independent IRB?

Can this be accomplished without

compromising military or national

security?

(b) Should the authority to make the

‘‘feasibility determination’’ (i.e.,

whether obtaining informed consent is

‘‘not feasible’’) under the interim rule be

vested in persons or entities other than

the Commissioner of FDA?

(c) Should the rule be more specific

in describing the information that must

be supplied to military personnel, or

should FDA have wide latitude to make

such determinations on a case-by-case

basis?

(d) Should additional measures be

taken to insure that information

required by FDA is effectively conveyed

to the affected military personnel? If so,

what should these measures be?

(e) Should the rule address what

constitutes adequate recordkeeping and

adequate long term followup of

individuals who receive investigational

products? If so, in what way?

(f) Should the rule contain additional

procedures to enhance understanding,

oversight, and accountability? If so,

what are these procedures?

(g) Should the rule contain additional

procedures to track noncompliance?

B. When Is It Ethical to Expose

Volunteers to Toxic Chemical and

Biological Agents to Test the

Effectiveness of Products That May Be

Used to Provide Potential Protection

Against Those Agents?

The agency recognizes that reliance

on nonhuman studies will almost

always give greater uncertainty about

effectiveness than would studies in

humans. Therefore, the agency is also

seeking comments on the ethical and

scientific considerations of conducting

human efficacy trials with these

products. For example, the agency is

interested in receiving comment on

whether it is ethical to conduct

challenge studies in humans if, should

the test product fail, there is strong

reason to believe the effect of the

challenge could be reversed or

effectively treated. What if the effect of

the challenge could not be reversed or

effectively treated? What would be the

needed risk/benefit assessment? Who

could volunteer for such studies? Would

it be ethically preferable to carry out

such studies in people who could be

exposed to the toxic substance? Should

the agency further explore these issues

in a separate public forum?

C. If Products That May Be Used to

Provide Potential Protection Against

Toxic Chemical and Biological Agents

Cannot Be Ethically Tested in Humans,

What Evidence Would Be Needed to

Demonstrate Their Safety and

Effectiveness?

(1) Should FDA identify the evidence

needed to demonstrate safety and

effectiveness for drugs that cannot

ethically be tested on humans to

demonstrate efficacy when such tests

would involve administering a severely

toxic substance to human volunteers? If

‘‘yes,’’ what should constitute the

evidence needed to demonstrate safety

and efficacy? (The current statutory

standard requires, among other things,

there be ‘‘substantial evidence’’ that the

drug is effective; ‘‘substantial evidence’’

means evidence ‘‘consisting of adequate

and well-controlled investigations,

including clinical investigations * * *

on the basis of which it could fairly and

responsibly be concluded by such

experts that the drug’’ is effective.)

(2) If the agency were to identify the

evidence needed to demonstrate safety

and effectiveness of these products,

would this preclude the need for the

interim rule? What specific advantages

would this offer over the interim rule?

(3) Civilian populations may require

products used in the prevention or

treatment of the serious or lifethreatening effects from exposure to

toxic chemical or biological agents, e.g.,

in the event of exigencies such as the

release of toxic chemical agents in the

Tokyo subway system. Thus, should the

agency consider identifying the

evidence needed to demonstrate safety

and effectiveness for these products

which would apply to both civilian as

well as military populations?

Dated: July 7, 1997.

Michael A. Friedman,

Lead Deputy Commissioner for the Food and

Drug Administration.

[FR Doc. 97–20311 Filed 7–29–97; 10:58 am]

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