Human Drugs and Biologics; Determination That Informed Consent Is NOT Feasible or Is Contrary to the Best Interests of Recipients; Revocation of 1990 Interim Final Rule; Establishment of New Interim Final Rule

SUMMARY: The Food and Drug Administration (FDA) is revoking its 1990

interim final regulations 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. FDA also is issuing a new interim final rule addressing waiver

of informed consent in military operations. FDA is taking these actions

based on its analysis and consideration of all relevant facts,

including its evaluation of the Department of Defense's (DOD)

experience during the Persian Gulf War, its evaluation of the comments

received by the agency in response to the agency's July 31, 1997,

request for comments on whether the agency should revise or revoke the

interim regulations, and the enactment of the Strom Thurmond National

Defense Authorization Act for Fiscal Year 1999 (the Defense

Authorization Act). Under the Defense Authorization Act, the President

is authorized to waive the Federal Food, Drug, and Cosmetic Act's (the

act) informed consent requirements in military operations if the

President finds that obtaining consent is infeasible or contrary to the

best interests of recipients and on an additional ground that obtaining

consent is contrary to national security interests. In light of the

enactment of the Defense Authorization Act, with an immediate effective

date, and because the President could be called upon to make a waiver

determination for military personnel engaged in a specific military

operation at any time, the agency believes that it is critical to have

in place adequate criteria and standards for the President to apply in

making an informed consent waiver determination. Therefore, FDA is

issuing a new interim final regulation with an immediate effective date

to establish criteria and standards for the President to apply in

making a determination that informed consent is not feasible or is

contrary to the best interests of the individual recipients.

DATES: Effective October 5, 1999. Submit written comments by December

20, 1999.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,

Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Bonnie M. Lee, Division of Compliance

Policy, Office of Enforcement, Office of Regulatory Affairs (HFC-230),

Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857,

301-827-0415.

SUPPLEMENTARY INFORMATION:

I. Background

FDA is revoking its interim final regulations related to informed

consent for human drug and biological products that permitted 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. On a case-

by-case basis, the interim final rule authorized the Commissioner to

make such a determination at the written request of the Assistant

Secretary of Defense (Health Affairs). Any determination made with

respect to the nonfeasibility of obtaining informed consent expired at

the end of 1 year, unless renewal was requested, or when DOD informed

the Commissioner that the military operation had ended, whichever was

earlier.

In the Federal Register of July 31, 1997 (62 FR 40996), FDA

published a document entitled ``Request for Comments'' that discussed

the use of investigational drugs and biologicals in military and other

emergency settings to treat or prevent toxicity of chemical or

biological substances (hereinafter referred to as the July 1997 request

for comments). In this document, FDA provided extensive background on

the development and implementation of the 1990 interim rule and DOD's

experience during the Persian Gulf War. The agency's request for

comments included specific questions in the three following subject

areas.

First, the agency asked whether its rule permitting waiver of

informed consent in very limited circumstances involving military

exigencies should be revoked or amended, and if so, how. In 1990, FDA

issued an interim rule (``Informed Consent for Human Drugs and

Biologics; Determination that Informed Consent is Not Feasible''

(Sec. 50.23(d) (21 CFR 50.23(d)) (55 FR 52814, December 21, 1990)),

allowing the Commissioner to make the determination, in response to

product specific requests from DOD, that obtaining informed consent

from military personnel for the use of an investigational drug or

biological product is not feasible in certain battlefield or combat-

related situations.

Second, because information on a product's efficacy in reducing or

preventing toxicity of chemical or biological substances is important,

the agency also asked when, if ever, it is ethical to expose volunteers

to toxic chemical and biological substances to test the efficacy of

products that may be used to provide potential protection against those

substances.

Third, because these products are critically important, even if

they cannot be ethically tested in humans to demonstrate efficacy, the

agency asked what evidence of efficacy, other than that from human

trials, would be appropriate to demonstrate the safety and efficacy of

products that may provide protection against toxic chemical and

biological substances.

In a related document published elsewhere in this issue of the

Federal Register, FDA has addressed the second and third issues in a

proposed regulation that discusses the evidence needed to demonstrate

efficacy of new drugs for use against lethal or permanently disabling

toxic substances when definitive efficacy studies in humans cannot

ethically be conducted. The agency believes that, if issued, this

proposed rule may make it possible to develop evidence sufficient to

support approval of such drugs and thus should help minimize the need

to use investigational products in military exigencies.

With respect to the first question, waiver of informed consent in

military operations, FDA's decision to revoke the 1990 interim rule is

based on consideration of all relevant facts, including FDA's

evaluation of DOD's experience during the Persian Gulf War, FDA's

analysis of the comments received in response to the first issue

addressed in the July 1997 request for comments on whether the agency

should revise or revoke the interim rule (62 FR 40996), and the recent

enactment of the Defense Authorization Act.

Section 731 of the Defense Authorization Act, amending 10 U.S.C.

[[Page 54181]]

1107(f), became effective on October 17, 1998. Under 10 U.S.C. 1107(f),

the Commissioner of Food and Drugs no longer has the authority to make

waiver of informed consent decisions in military operations because 10

U.S.C. 1107(f)(1) explicitly vests the authority to waive the act's

informed consent requirement in the President. Section 1107(f)(1) of

Title 10 provides for such waiver in the case of the administration of

an investigational new drug or drug unapproved for its applied use to a

member of the armed forces in connection with the member's

participation in a particular military operation. Section 1107(f)(1) of

Title 10 authorizes the President to waive informed consent if the

President finds that obtaining informed consent is: (1) Not feasible;

(2) contrary to the best interests of the member; or (3) not in the

interests of national security. The first two grounds (lack of

feasibility or contrary to the best interests of recipients) are

specified in section 505(i) of the act (21 U.S.C. 355(i)).

Section 1107(f)(2) of Title 10 provides that, in making a

determination to waive informed consent on the grounds that it is not

feasible or contrary to the best interests of the armed services

member, the President shall apply the standards and criteria that are

set forth in the relevant FDA regulations for a waiver of the prior

consent requirement on that ground.

Because section 1107(f)(1) of Title 10 refers to waiver of

informed consent in connection with military operations, the relevant

FDA regulations referenced in section 1107(f)(2) of Title 10 would be

any regulations dealing with waivers in this context. As discussed

previously, FDA originally issued such regulations as an interim final

rule in 1990 (55 FR 52814, December 21, 1990), at Sec. 50.23(d)(1)

through (d)(4). These regulations consisted of procedures to be

followed by the Assistant Secretary of Defense (Health Affairs) and the

Commissioner of Food and Drugs (Sec. 50.23(d)(1)); standards and

criteria for granting such waivers (Sec. 50.23(d)(1) and (d)(2)); a

discretionary provision for consultation with advisory committees

(Sec. 50.23(d)(3)) and time limits for such waivers (Sec. 50.23(d)(4)).

These regulations conflict with section 1107(f)(1) of Title 10 in that

they vest FDA's Commissioner with the authority to make such waiver

decisions.

As reflected in a number of the comments FDA received on the 1990

interim rule, many people addressed the issue of whether waiver of

informed consent in military operations involving military personnel is

ever acceptable, and if so, when. In the Defense Authorization Act,

Congress has addressed that issue by explicitly providing for waiver of

the informed consent requirement by the President in certain

situations. In light of the immediate effective date of the Defense

Authorization Act, the agency believes that it is critical to have in

place adequate criteria and standards for the President to apply in

making an informed consent waiver determination.

Based on the extensive examination of issues associated with the

existing interim final rule during the last 8 years, the agency has

developed a new rule consistent with the Defense Authorization Act that

contains new strengthened criteria and standards that the President can

use in making informed consent waiver determinations. The agency

believes that it is in the public interest to have these new criteria

and standards in place and available for use should the President be

called upon to make a waiver determination while, at the same time, it

solicits public comments on these criteria and standards. These new

criteria and standards are discussed in greater detail later in this

document.

II. Comments Received on Whether to Revoke or Amend the 1990

Interim Rule

The agency received 134 comments on whether it should revoke or

amend the 1990 interim rule: Of these, 119 comments expressed

opposition to the interim rule and recommended that it be permanently

revoked, 7 comments recommended changes to the interim rule, 2 comments

supported retention of the interim rule, and 6 comments misunderstood

the scope of the interim rule and provided comments on a different

regulation.

A. Summary of Comments Recommending That the Interim Rule Be Revoked

The 119 comments that recommended the revocation of the interim

rule were signed by 160 individuals including veterans, veterans'

relatives, active military personnel, active military families,

ethicists, physicians, other health care providers, and private

citizens, as well as from an advocacy group for ailing Persian Gulf

Veterans, an organization representing grassroots veterans'

organizations in America and England, and a nonprofit public interest

organization.

Most of these comments opposed the agency's continued use of the

interim rule after the experience of the Persian Gulf War. Many thought

it should never have been used. Specifically, 114 comments stated that

informed consent was absolutely essential and that military personnel,

like other nonmilitary citizens, should receive adequate information

about an investigational product before its use and have the right to

refuse to receive it. Seventeen comments stressed the need for followup

of possible adverse reactions to investigational products, and 15

comments indicated that DOD could not fulfill its responsibilities even

if FDA required adequate followup and other requirements as part of a

new regulation. Five comments stated that DOD had shown itself to be

incapable of adequate oversight and recordkeeping and three comments

noted that the interim rule had not been implemented by DOD as had been

intended. Several comments suggested that if the rule were to be used

again, there must be an independent board of medical and ethical

experts, there must be an institutional review board independent of

DOD, and there must be proper monitoring that could only be done by

non-DOD personnel.

As described earlier in this document, The Defense Authorization

Act answers the controversial question of whether waiver of informed

consent in military operations is ever appropriate. In passing this

legislation, Congress has concluded that the President may waive the

informed consent requirement for military personnel engaged in a

particular military operation in certain situations. The comments on

the 1990 interim rule pointed out significant areas that needed to be

strengthened, including: Provision of adequate information about an

investigational product before its use; adequate followup to assess

whether there are adverse health consequences that result from the use

of the investigational product; adequate oversight, accountability, and

recordkeeping when investigational agents are used; and involvement of

non-DOD personnel in decisions to use investigational products without

informed consent. All of these areas have been addressed in the new

interim rule that establishes the criteria and standards for the

President to use in making an informed consent waiver determination.

B. Summary of Comments Recommending Changes to the Interim Rule

Seven comments recommended changes to the interim rule. Three of

these comments recommended that the rule be suspended and reconsidered

only if their modifications were adopted and adhered to by DOD.

Two comments recommended that a process be established for the

President

[[Page 54182]]

to authorize the use of investigational products without informed

consent in military conflicts.

The Defense Authorization Act establishes the President as the

sole authority for making a waiver of informed consent determination

for military personnel involved in a particular military operation.

Thus, the process recommended by these comments has already been

established through legislation. FDA will be involved in this process

through its traditional role of reviewing specific protocols under its

investigational new drug (IND) regulations.

One comment recommended that the rule be amended to require: (1)

That reasonable efforts be made to inform individuals in advance that

investigational products are to be used, (2) that the extent and

appropriateness of the information provided be determined by the

Commissioner of FDA, (3) that all individuals exposed to

investigational products be informed no later than 1 year after their

use, and (4) that there be established a publicly accessible site for

continuous access to the most updated scientific information on these

products.

The agency agrees with this comment and has incorporated the

suggested requirements into the new interim rule. The interim rule

requires that each member involved in the military operation be given,

prior to the administration of the investigational new drug, a specific

written information sheet. That information sheet is to include

information (in addition to information required by 10 U.S.C. 1107(d))

concerning the investigational new drug, the risks and benefits of its

use, potential side effects, and other pertinent information about the

appropriate use of the product. Under 10 U.S.C. 1107(d), the

information sheet is required to contain the following: (1) Clear

notice that the drug being administered is an investigational new drug

or a drug unapproved for its applied use; (2) the reasons why the

investigational new drug or drug unapproved for its applied use is

being administered; (3) information regarding the possible side effects

of the investigational new drug or drug unapproved for its applied use,

including any known side effects possible as a result of the

interaction of such drug with other drugs or treatments being

administered to the members receiving such drug; and (4) such other

information that, as a condition of authorizing the use of the

investigational new drug or drug unapproved for its applied use, the

Secretary of Health and Human Services may require to be disclosed. FDA

intends to review the information sheet as part of its review of the

use of the investigational product under an IND in order to determine

its adequacy. The interim rule also requires DOD to provide public

notice in the Federal Register describing each waiver of informed

consent determination, a summary of the most updated scientific

information on the products used, as well as other pertinent

information.

One comment from an individual who was employed at the U.S. Army

Medical Materiel Development Activity, Ft. Detrick, MD, during the Gulf

War, and who served for 22 years as an Army officer, stated that ``[a]s

the largest training organization in the United States, perhaps in the

world, DoD clearly has the capacity and resources to provide adequate

information to each service member before he or she takes or uses an

investigational product.'' Based on this reasoning, the Army officer

suggested that the rule be amended and that DOD could, and should,

institute training programs early in each service member's military

career. Specifically, this comment recommended that FDA demand adequate

training as part of the informed consent process and require that DOD

develop and validate training guidelines for the use of investigational

products that might be used under a waiver during all phases of product

development.

The agency agrees with this comment. The interim rule now requires

DOD to provide training to the appropriate medical personnel and

potential recipients on the specific investigational new drug to be

administered prior to its use.

Two comments stressed that FDA should regard itself as acting on

behalf of the troops, not on behalf of the military or the DOD. These

comments recommended that the interim rule be suspended or revoked

until the agency critically reviewed requests from DOD to waive

informed consent that contained the following documentation: (1)

Documentation from DOD that identified the threat, its nature, and its

likelihood; (2) documentation from DOD that administration of the

proposed treatment is likely to be effective against that threat; (3)

documentation from DOD that detailed concurrent conditions (such as

environmental and occupational conditions, treatment regimens that may

be employed by troops serving in the forces to be treated) that could

alter the effects of the proposed treatment; (4) documentation from DOD

that demonstrated that military medical services are capable of

delivering qualified personnel and adequate supplies of necessary

medical material to the specific theater of operations; (5)

documentation from DOD that establishes that the recordkeeping systems

are capable of tracking the proposed treatment from supplier to point

of administration; and (6) documentation that demonstrates that there

are medical followup plans for troops receiving the proposed treatment.

These comments stated that this documentation should be made public and

public comment should be sought regarding the performance of both DOD

and FDA. These comments stated that if these requirements could be met,

adequate information would need to be provided to the troops by

individuals with whom they have daily contact.

The agency agrees with the suggestions for documentation contained

in these comments and has incorporated them into the new interim rule.

Under the new interim rule, each member involved in the military

operation will be given, prior to the administration of the

investigational new drug, a specific written information sheet. This

information sheet is required, under 10 U.S.C. 1107(d), to contain

specific information. The interim rule incorporates this requirement by

reference and requires the disclosure of risks and benefits of the use

of the investigational product, potential side effects, and other

pertinent information about the appropriate use of the product.

C. Comments in Support of Retaining the Interim Rule

The agency received two comments in support of retaining the

interim rule as written--one from DOD and the other from a physician

from academia. This latter comment stated that:

[t]he organization and activities of the DOD are not meant to be

either democratic or reliant upon informed consent. However, the

goal of DOD activities in combat situations is victory, and with

that end in sight, it is reasonable to expect that the condition of

the troops is considered carefully by DOD leadership. Decisions

pertinent to the use of investigational drugs without informed

consent will most likely represent the best interests of military

personnel and the nation.

DOD's comments in support of maintaining the interim rule were

similar to those expressed by DOD in requesting the interim rule

initially (see the Assistant Secretary of Defense (Health Affairs)

letter of October 30, 1990, to the Assistant Secretary for Health, HHS,

quoted in the preamble to the interim rule (55 FR 52814), and in its

September 13, 1996, response to the

[[Page 54183]]

May 7, 1996, petition to FDA requesting that the Commissioner repeal

the interim rule (see summary in the July 1997 request for comments (62

FR 40996 at 41000)).

As previously stated, Congress now has passed legislation

providing for waiver of the informed consent requirement by the

President in certain military situations, thus, recognizing the need

for waiver in limited situations. The agency, however, believes that

the criteria and standards contained in the 1990 interim rule are not

sufficient and has therefore established new criteria and standards for

the President to apply in making an informed consent waiver

determination.

D. Other Comments on the Interim Rule

A comment from Chairman Arlen Specter and Ranking Minority Member

John D. Rockefeller IV, Senate Committee on Veterans' Affairs, stated

that whether the rule should be revoked or not ``* * * is a complex

decision that needs to be carefully considered, with input from health

care professionals, ethicists, active duty military personnel,

veterans, and the general public.'' They urged FDA, if it decided not

to revoke the rule, to ensure that a process is instituted to provide

maximum protection to ``* * * the health and well-being of military

personnel prior to, during, and subsequent to a combat situation.''

They stressed the importance of establishing a process prior to any

combat situation that would: (1) Lay out how decisions would be reached

in a timely manner; (2) require institutional review boards (IRB's)

used during this process to consist of at least three persons

independent of DOD because the IRB will be making decisions that result

in the loss of rights of a large group of individuals and objectivity

is essential; (3) require health surveillance data from well-designed

data collection forms be used to assess the potential health

consequences of the use of products and to modify decisions as

information is gained; and (4) require compliance with mechanisms for

review and sanctions be put in place.

The agency agrees that the decisions associated with the interim

rule have been complex and there is a need to institute a process that

will provide maximum protection to military personnel. The Defense

Authorization Act vests authority in the President to make a waiver of

informed consent determination, and it vests in the President the

process by which such decisions shall be made. FDA believes that this

process, which includes use of the criteria and standards in the new

interim final rule, will provide the protection of the health and well-

being of military personnel urged by the comments. As suggested by this

comment, the new interim rule requires the IRB to include at least

three nonaffiliated members who are not employees or officers of the

Federal Government.

In response to the suggestion that the rule require health

surveillance to assess the potential health consequences of the use of

the product and to modify decisions as information is gained, the new

interim rule contains two provisions. One requires DOD to provide

adequate followup to assess whether there are beneficial or adverse

health consequences that result from the use of the investigational

product. The second requires DOD to report to FDA and to the President

any changed circumstances relating to the standards and criteria

contained in the rule or that otherwise might affect the determination

to use an investigational new drug without informed consent.

In response to the comment's recommendation that the process

require compliance with mechanisms for review and sanctions, the agency

notes that the Defense Authorization Act requires the Secretary of

Defense, if the President grants the requested waiver, to submit to the

chairman and ranking minority member of each congressional defense

committee a notification of the waiver, together with the written

determination of the President and the Secretary of Defense's

justification for the request for the waiver of informed consent (see

10 U.S.C. 1107(f)(3)(B)). The new interim rule builds in accountability

and compliance by requiring the Secretary of Defense to certify and

document to the President that the standards and criteria in the rule

have been met, including the criteria that use of the investigational

drug without informed consent otherwise conforms with applicable law.

Further, the new interim rule notes that ``[n]othing in these criteria

or standards is intended to preempt or limit FDA's and DOD's authority

or obligations under applicable statutes and regulations.'' The agency

notes that the mechanisms for review and sanctions under the IND

regulations apply to the DOD and its employees involved in the use of

products subject to FDA regulation.

In response to the comment's suggestion that the process include

public disclosure, the new interim rule requires DOD to provide public

notice in the Federal Register as soon as practicable and consistent

with classification requirements describing each waiver of informed

consent determination, a summary of the most updated scientific

information on the products used, and other pertinent information.

The agency has concluded that the issues associated with the 1990

interim rule are very complex and difficult, as recognized by Senators

Specter and Rockefeller. As described in detail in FDA's July 1997

request for comments, there has been extensive examination of issues

associated with the 1990 interim rule during the last 8 years. In

addition to FDA's July 1997 request for comments, the issues have been

examined in comments submitted to the agency in the 30-day comment

period following the rule's publication in the Federal Register on

December 21, 1990; in litigation (Doe v. Sullivan, 756 F. Supp. 12, 14

(D.D.C. 1991)); in a May 6, 1994, United States Senate Committee on

Veterans' Affairs hearing on ``Is Military Research Hazardous to

Veterans' Health? Lessons From World War II, the Persian Gulf, and

Today;'' reviews conducted by the Presidential Advisory Committee on

Gulf War Veterans' Illnesses; and in the Public Citizen, the National

Veterans Legal Services Program, and the National Gulf War Resource

Center, Inc., May 7, 1996, petition to FDA requesting that the

Commissioner repeal the interim rule.

The agency believes that exceptions from the informed consent

requirement should apply rarely and only when sufficient additional

protections are provided to the military personnel affected.

III. Revocation of the 1990 Interim Rule

The agency recognizes that there may be future military combat

situations where U.S. military personnel are at risk of exposure to

chemical and biological weapons and that DOD has a critical and

legitimate interest in protecting military personnel from such chemical

and biological agents. This was the basis for FDA's 1990 interim rule

issued in anticipation of the Persian Gulf War that gave DOD the

authority to use specified investigational products to provide

potential protection against chemical and biological warfare agents

without obtaining informed consent from individual service personnel.

A. DOD's Experience in Implementing the Rule During the Persian Gulf

War

DOD's experience during the Gulf War with pyridostigmine bromide

and the botulinum toxoid vaccine was described in detail in the July

1997 request for comments (62 FR 40996 at 40998 through 41000). A brief

summary of this experience follows.

[[Page 54184]]

In December 1990, DOD submitted protocols under IND's and requests

for waiver of informed consent for: (1) Pyridostigmine bromide 30-

milligram tablets, a potentially useful pretreatment against soman, a

nerve gas; and (2) the botulinum toxoid vaccine, potentially protective

against toxins produced by Clostridium botulinum (the bacterium that

produces the toxin that causes botulism). The Commissioner approved

both of DOD's waiver requests and each product was administered to some

of the military personnel who participated in Operation Desert Storm.

FDA's agreement to waive the informed consent requirement was based, in

large part, on DOD's agreement to provide and disseminate specified

information on these products to military personnel and upon adherence

to labeling and other prescribed requirements for the use of

investigational products.

Concurrent with the agency's request for comments on the interim

rule, FDA was also evaluating DOD's experience in implementing IND's,

as well as waivers under the interim rule, during the Gulf War in order

to obtain specific factual information and to assess DOD's compliance

with FDA requirements. In the agency's ongoing evaluation of the use of

investigational products in the Persian Gulf, the agency identified

significant deviations from Federal regulations published in Title 21,

Code of Federal Regulations (CFR), parts 50 and 312 (21 CFR parts 50

and 312). These deviations were set forth in a July 22, 1997, and a

December 2, 1997, letter from the Lead Deputy Commissioner of the Food

and Drug Administration to the Acting Deputy Secretary of Defense for

Health Affairs (Refs. 1 through 3). The noted deviations, and the

relevant observations that formed the basis for the conclusion that

deviations had occurred, are summarized in the following paragraphs.

1. Pyridostigmine Bromide

There was a failure to meet the conditions set by the Commissioner

for granting a waiver from the informed consent requirements under the

1990 interim rule for pyridostigmine bromide. FDA's agreement to waive

the informed consent requirement at the time of the Gulf War was based,

in large part, on DOD's agreement to provide and disseminate

information on pyridostigmine to all military personnel. Based on DOD

statements to FDA as well as FDA's own evaluation, FDA has concluded

that the information sheet on pyridostigmine was not provided and

disseminated to military personnel in the Gulf as required by the

Commissioner's letter granting the waiver under the interim rule.

Because inadequate information was provided to the soldiers, at least

some soldiers either took the wrong amount of pyridostigmine or

disregarded orders to take it completely.

There was a failure to collect, review, and make reports of

adverse experiences attributed to the use of pyridostigmine bromide in

a timely manner. Although the agency waived the requirements of

Sec. 312.32 in regard to the 3- and 10-day time limits for the

reporting of adverse experiences, the agency expected DOD to make a

reasonable effort to collect, review, and make reports of adverse

clinical consequences attributed to the use of the product in as timely

a manner as conditions permitted.

There was a failure to label pyridostigmine bromide with

investigational labeling as required by FDA regulations. FDA had

agreed, as requested by DOD, to waive the provisions of Sec. 312.6 in

order to allow DOD to employ the phrase ``For military use and

evaluation'' in place of the statement ordinarily mandated for use on

the immediate package of an investigational drug product, which reads

``Caution: New Drug--Limited by Federal (or United States) Law to

Investigational Use''. FDA's waiver of the standard statement was on

condition that all of the product distributed to service members would

carry the new ``military use'' labeling. Based on information provided

to the agency, FDA believes that the pyridostigmine bromide distributed

to military personnel in the Persian Gulf was not labeled as required

by the conditions of the waiver.

2. Botulinum Toxoid Vaccine

There was a failure to ensure that the investigation was conducted

in accordance with the general investigational plan for the botulinum

toxoid vaccine during the Gulf War. The protocol for the botulinum

toxoid vaccine stated that each botulinum toxoid vaccine dose was to be

recorded in the individual's permanent immunization record. This was

not done.

There was also a failure to maintain adequate records showing the

receipt, shipment, and disposition of the investigational product

botulinum toxoid vaccine as required by Secs. 312.57 and 312.59.

On January 8, 1991, FDA granted DOD's request for a waiver of

informed consent under the interim final rule for use of the botulinum

toxoid vaccine during the Gulf War. However, following the cessation of

combat activities DOD advised FDA in a March 15, 1991, letter that the

military command in the theater of operations in the Persian Gulf

decided to administer the botulinum toxoid vaccine on ``a voluntary

basis.'' This letter did not state whether informed consent was

obtained.

The military command's decision to allow administration of the

vaccine on a voluntary basis indicates that the criteria for granting a

waiver under the interim rule was no longer met; specifically that ``*

* * preservation of the health of the individual and the safety of

other personnel require that a particular treatment [botulinum toxoid

vaccine] be provided to a specified group of military personnel,

without regard to what might be an individual's personal preference for

no treatment or for some alternative treatment.'' If the criteria for

waiver were not met, DOD was required to obtain and document the

informed consent of military personnel receiving the vaccine in

accordance with Secs. 50.25 and 50.27. Without signed consent forms to

document that informed consent was obtained, and based on testimony

from Persian Gulf War veterans that information on the vaccine was not

uniformly given to military personnel, the agency has concluded that

informed consent was not routinely obtained from military personnel who

received the botulinum toxoid vaccine in accordance with FDA

regulations.

Experience with the use of the waiver provision of the 1990

interim rule suggests two conclusions: (1) To the extent possible,

military personnel should receive treatments whose safety and

effectiveness have been fully evaluated; (2) where it is necessary to

utilize investigational agents and to waive informed consent, new

standards and criteria for doing so should be developed that will

better ensure protection of the troops receiving the investigational

product.

B. Future Use of FDA-Regulated Products by DOD

FDA has concluded that there are important ways for the agency to

contribute to DOD's mandate to protect military personnel that are

consistent with FDA's mission and regulations. FDA's existing

mechanisms for providing access to investigational products under an

IND will continue to be available to any entity that complies with the

agency's specified requirements. Both DOD and FDA recognize, however,

that some of the IND requirements may not be feasible in certain combat

situations. Based on the lessons from use of investigational agents

during the Gulf War, the agency

[[Page 54185]]

believes that DOD's needs can best be met through DOD's support of drug

development efforts leading to approval of products found to be safe

and effective.

FDA shares DOD's goal of getting the best products to military

personnel. Thus, FDA is committed to working with DOD to resolve the

safety and effectiveness questions that may allow FDA to approve the

drug and biological products for use in military operations and during

military exigencies. In order to provide pharmaceutical agents that are

safe and effective in protecting military personnel, the agency

believes that DOD must focus its efforts on drug development. The

agency notes that under existing regulations it can expedite access to

new drugs by accelerating approval (subpart H of 21 CFR part 314 and

subpart E of 21 CFR part 601). In addition, consistent with the recent

changes to the act on fast track products made in the Food and Drug

Administration Modernization Act of 1997, FDA is committed to

facilitating development and expediting the review of drugs for serious

and life-threatening conditions that address unmet needs (section 506

of the act (21 U.S.C. 356)). Moreover, FDA is proposing an additional

mechanism for product approval that is described elsewhere in this

issue of the Federal Register and that relates to the evidence needed

to demonstrate safety and efficacy for drug and biological products for

use against lethal or toxic substances when efficacy studies in humans

cannot ethically be conducted.

In order to minimize the need to use investigational products

during military exigencies, DOD and FDA have formed a working group for

the purpose of assisting DOD in its drug development efforts related to

these products. DOD has agreed to identify those products that may

provide protection to military members, develop appropriate drug

development plans for each product, and establish a timeframe for

completion.

FDA recognizes, however, that in rare instances investigational

products may need to be used by DOD in deployment situations. The

enactment of the Defense Authorization Act reflects this fact and calls

for the implementation of a process that will help ensure that when

informed consent is waived it will be done under standards and criteria

that will help protect the troops receiving the investigational

product. Accordingly, FDA has issued this new interim rule.

IV. Establishment of New Standards and Criteria

A. Description of New Interim Rule

As described earlier, under 10 U.S.C. 1107(f), the President may

waive the prior consent requirement for the administration of an

investigational new drug to a member of the armed forces in connection

with the member's participation in a particular military operation. The

statute specifies that only the President may waive informed consent

and that the President may grant such a waiver only if the President

determines in writing that obtaining consent: Is not feasible, is

contrary to the best interests of the military member, or is not in the

interests of national security. The statute further provides that in

making this determination based on the grounds that it is infeasible or

contrary to the best interests of the military member, the President

shall apply the standards and criteria that are set forth in the

relevant FDA regulations for a waiver of the prior informed consent

requirements. This interim rule contains those standards and criteria.

The statute is silent about the standards and criteria that the

President is to apply in making a determination that obtaining consent

is not in the interests of national security.

The Defense Authorization Act authorizes the Secretary of Defense

to request an informed consent waiver determination from the President.

The interim rule requires the Secretary of Defense to certify and

document to the President that the standards and criteria in the

interim rule have been met.

Section 50.23(d)(1)(i) through (d)(1)(iv) contain the fundamental

information necessary to make an informed assessment of risks and

benefits. Under these paragraphs, the Secretary of Defense must certify

and document that: (1) The extent and strength of evidence of the

safety and effectiveness of the investigational new drug in relation to

the medical risk that could be encountered during the military

operation supports the drug's administration under an IND; (2) the

military operation presents a substantial risk that military personnel

may be subject to a chemical, biological, nuclear, or other exposure

likely to produce death or serious or life-threatening injury or

illness; (3) there is no available satisfactory alternative therapeutic

or preventive treatment in relation to the intended use of the

investigational new drug; and (4) conditioning use of the

investigational new drug on the voluntary participation of each member

could significantly risk the safety and health of any individual member

who would decline its use, the safety of other military personnel, and

threaten the accomplishment of the military mission.

The requirements for IRB review of protocols for military use of

investigational drugs without informed consent have been strengthened

and further specified. Following the Gulf War, the agency became aware

that a military IRB, upon initial review of the proposed use of the

botulinum toxoid vaccine in anticipation of the Gulf War, had

recommended that the vaccine be provided with informed consent (Ref.

4). The proposed use was subsequently reviewed by a different military

IRB that approved its use without informed consent. It is not clear

whether the conclusions of the initial IRB were shared with the

subsequent IRB. In order to ensure adequate and meaningful IRB review,

Sec. 50.23(d)(1)(v) requires the duly constituted IRB to be responsible

for the review of the study and requires that the IRB review and

approve the investigational new drug protocol and the administration of

the investigational new drug without informed consent as a prerequisite

for the study to proceed. It also requires DOD's request for a waiver

to include the documentation of minutes of IRB meetings at which the

protocol was reviewed. This documentation of minutes is required by 21

CFR 56.115(a)(2).

Section 50.23(d)(2) describes additional requirements that pertain

to this IRB that are not contained in FDA's IRB regulations part 56 (21

CFR part 56). The IRB must include at least 3 nonaffiliated members who

are not employees or officers of the Federal Government (other than for

purposes of membership on the IRB). The quorum required for a convened

meeting must include a majority of the members including at least one

member whose primary concerns are in nonscientific areas, and, if

feasible, a majority of the nonaffiliated members. The minutes of IRB

meetings at which the protocol is reviewed are to be provided to the

Secretary of Defense for further review.

Section 50.23(d)(3) describes additional review requirements that

pertain to this IRB. For the study to be able to proceed, the IRB must

review and approve the contents of the required written information

sheet on the investigational product; the adequacy of the plan to

disseminate information, including the information sheet and other

information (e.g., in forms other than written), to potential

recipients; the adequacy of the information and the plans for its

dissemination to health care providers, including potential side

[[Page 54186]]

effects, contraindications, potential interactions, and other pertinent

considerations; and an informed consent form, as required by part 50,

in those circumstances in which DOD determines that informed consent

may be obtained from some or all personnel involved. In addition,

Sec. 50.23(d)(4) requires DOD to submit to FDA summaries of IRB

meetings at which the proposed protocol has been reviewed.

In order to help ensure that the President is provided all

relevant information related to the effects of the investigational

drug, Sec. 50.23(d)(1)(vi) requires the Secretary of Defense to certify

and document in his or her request for a waiver determination under

Sec. 50.23(d)(1) that DOD has explained: (1) The context in which the

investigational drug will be administered; (2) the nature of the

disease or condition for which the preventive or therapeutic treatment

is intended; and (3) to the extent there are existing data or

information available, information on conditions that could alter the

effects of the investigational drug.

In order to help ensure better recordkeeping than occurred during

the Gulf War, Sec. 50.23(d)(1)(vii), (d)(1)(ix), and (d)(1)(x) require

the Secretary of Defense to document and certify that DOD's

recordkeeping system is capable of tracking, and will be used to track

the proposed treatment from the supplier to the individual recipient;

that medical records of members involved in the military operation will

accurately document the receipt by members of the notification required

by Sec. 50.23(d)(1)(viii) as well as any investigational new drugs in

accordance with FDA regulations.

In order to help ensure that each military member is provided

adequate information on the investigational product,

Sec. 50.23(d)(1)(viii) requires the Secretary of Defense to document

and certify that each member involved in the military operation will be

given, prior to the administration of the investigational new drug, a

specific written information sheet containing specified information.

Section 50.23(d)(1)(xiv) requires the Secretary of Defense to document

and certify that DOD will provide training to the appropriate medical

personnel and potential recipients on the specific investigational new

drug to be administered prior to its use.

In response to comments that DOD must provide adequate followup to

determine whether there are adverse consequences to the use of

investigational products, Sec. 50.23(d)(1)(xi) requires the Secretary

of Defense to document and certify that DOD will provide adequate

followup to assess whether there are beneficial or adverse health

consequences that result from the use of the investigational product.

Because the agency believes that exceptions to the informed

consent requirement should be made rarely and in narrow circumstances

and that it is preferable to establish the safety and efficacy of

products before their general use in large populations,

Sec. 50.23(d)(1)(xii) requires the Secretary of Defense to certify and

document that DOD is pursuing drug development for the investigational

drug (that could be used in a deployment situation), including a time

line for such development, and marketing approval with due diligence.

The rule contains two provisions to help ensure that informed consent

waiver determinations continue to meet the standards and criteria of

this rule after an initial waiver has been granted by the President.

Section 50.23(d)(1)(xv) requires the Secretary of Defense to certify

and document that DOD has stated and justified the time period for

which the waiver is needed, not to exceed 1 year. For a waiver to

exceed 1 year, this paragraph requires such a waiver to be separately

renewed under the standards and criteria contained in Sec. 50.23(d).

Section 50.23(d)(1)(xvi) places a continuing obligation on DOD to

report to the FDA and to the President any changed circumstances

relating to these standards and criteria or that otherwise might affect

the determination to use an investigational new drug without informed

consent.

Section 50.23(d)(1)(xiii) has been included in order to ensure

that FDA has completed its review of the investigational new drug

protocol and concluded that it may proceed subject to a decision by the

President on the informed consent waiver request. FDA will provide a

written notification to DOD after it has completed its review of the

investigational new drug protocol. This notification may either grant

permission for the protocol to proceed subject to the President's

decision on the informed consent waiver request or it may place the

study on clinical hold. DOD should not proceed with a protocol under

this rule until it has received notification from FDA that the protocol

may proceed. As discussed later in this document, the agency has

adopted a change in part 312 to help ensure that the IND review process

is efficiently applied to the use of investigational products under

this rule.

In response to a number of comments, discussed previously, that

encouraged public access to information about products for which an

informed consent waiver is granted, the agency has included

Sec. 50.23(d)(1)(xvii) in the rule. This paragraph requires DOD to

provide public notice as soon as practicable and consistent with

classification requirements through notice in the Federal Register

describing each waiver of informed consent determination, a summary of

the most updated scientific information on the products used, and other

pertinent information.

Finally, in order to help ensure that DOD adheres to applicable

statutes and laws, Sec. 50.23(d)(1)(xviii) requires the Secretary of

Defense to document and certify that the use of the investigational

drug without informed consent otherwise conforms with applicable law.

Section 50.23(d)(5) states that ``[n]othing in these criteria or

standards is intended to preempt or limit FDA's and DOD's authority or

obligations under applicable statutes and regulations.''

B. Description of Conforming Amendments

This interim rule necessitates a change to the regulations for

human drugs so that those regulations are consistent with this rule.

The agency is amending Sec. 312.42 to explicitly state that an

investigation may be placed on clinical hold pending a determination by

the President to waive the prior consent requirement for the

administration of an investigational new drug. If the agency invokes

this reason for a clinical hold, it will mean that the agency has

completed its review of the protocol and has concluded that the study

may proceed; however, subjects may not be enrolled in the study until a

positive decision on the informed consent waiver request has been made

by the President and FDA has provided written notification to DOD that

the clinical hold has been removed.

V. Request for Comments

Interested persons may, on or before December 20, 1999, submit to

the Dockets Management Branch (address above) written comments

regarding this rule. 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.

FDA is revoking the December 21, 1990, interim rule and issuing a

new interim rule in its place effective on date of publication in the

Federal Register. FDA is proceeding without notice and comment

rulemaking because of the

[[Page 54187]]

significant need to have regulations in place that are consistent with

recently enacted legislation addressing waiver of informed consent in

military operations and that provide adequate standards and criteria

for such waiver determinations. As described in more detail in the

following paragraphs, FDA finds, in accordance with section 553(b) of

the Administrative Procedure Act, that it would be impracticable and

contrary to the public interest to provide for notice and comment prior

to the revocation of the December 1990 rule and the issuance of the new

interim rule.

The statutory provision in the Defense Authorization Act that

vests authority for waiver decisions in the President overrides the

1990 rule vesting authority for such waiver decisions in the

Commissioner. Thus, it invalidates those parts of the 1990 regulation

that are inconsistent with the Defense Authorization Act. The new

interim rule corrects this inconsistency by acknowledging the existence

of the Defense Authorization Act and its grant of waiver authority to

the President. To require notice and comment to make this correction is

unnecessary in that the new rule codifies in regulation a clear

statutory mandate.

Since the issuance of the 1990 interim rule, there has been

extensive public discussion regarding the rule on numerous occasions

(see discussion in section II of this document). After considering all

the relevant facts, including the comments received on the July 1997

request for comments, and FDA's evaluation of DOD's experience during

the Persian Gulf War in implementing the 1990 rule, FDA has concluded

that the rule did not work as intended. In light of the enactment of

the Defense Authorization Act, with an immediate effective date and

because the President could be called upon to make a waiver

determination for military personnel engaged in a specific military

operation at any time, the agency believes that it is critical to have

in place adequate criteria and standards for the President to apply in

making an informed consent waiver determination. Modifying the 1990

rule to conform to the statute, without adding the additional

protections provided in this new rule is contrary to the public

interest because it would leave in place, during the comment period,

procedures now considered insufficient. As discussed previously, FDA

has developed new strengthened criteria and standards that the

President can use in making informed consent waiver determinations.

Accordingly, the agency believes it is in the public interest to have

these new criteria and standards in place while, at the same time, it

solicits public comment.

It is, therefore, in the public interest, to establish quickly,

through this new interim final rule, stringent criteria and standards

for the President's application. Following the comment period, the

agency intends promptly to publish a final rule.

VI. Environmental Impact

The agency has determined under 21 CFR 25.30(h) that this action is

of a type that does not individually or cumulatively have a significant

effect on the human environment. Therefore, neither an environmental

assessment nor an environmental impact statement is required.

VII. Executive Order 12612: Federalism

Executive Order 12612 requires Federal agencies to carefully

examine regulatory actions to determine if they would have a

significant effect on federalism. Using the criteria and principles set

forth in the order, FDA has considered the impact of the interim rule

on the States, on their relationship with the Federal Government, and

on the distribution of power and responsibilities among the various

levels of Government. FDA concludes that this rule is consistent with

the principles set forth in Executive Order 12612.

Executive Order 12612 states that agencies formulating and

implementing policies are to be guided by certain federalism

principles. Section 2 of Executive Order 12612 enumerates fundamental

federalism principles. Section 3 of Executive Order 12612 states that,

in addition to these fundamental principles, executive departments and

agencies shall adhere, to the extent permitted by law, to certain

listed criteria when formulating and implementing policies that have

federalism implications. Section 4 of Executive Order 12612 lists

special requirements for preemption.

Section 4 of Executive Order 12612 states that an executive

department or agency foreseeing the possibility of a conflict between

State law and federally protected interests within its area of

regulatory responsibility is to consult with States in an effort to

avoid such conflict. Section 4 of Executive Order 12612 also states

that an executive department or agency proposing to act through

rulemaking to preempt State law is to provide all affected States

notice and opportunity for appropriate participation in the

proceedings. As required by the Executive Order in section 4(d) and

(e), States have, through this notice of proposed rulemaking, an

opportunity to raise the possibility of conflicts and to participate in

the proceedings. Consistent with Executive Order 12612, FDA requests

information and comments from interested parties, including but not

limited to State and local authorities, on these issues of federalism.

VIII. Analysis of Impacts

FDA has examined the impacts of the rule under Executive Order

12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). Executive

Order 12866 directs agencies to assess all costs and benefits of

available regulatory alternatives and, when regulation is necessary, to

select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). If a rule would have a

significant economic impact on a substantial number of small entities,

the Regulatory Flexibility Act requires agencies to analyze regulatory

options that would minimize these impacts. Title II of the Unfunded

Mandates Reform Act (Public Law 104-4) (in section 202) requires that

agencies prepare an assessment of anticipated costs and benefits before

proposing any rule that may result in an expenditure in any 1 year by

State, local, and tribal governments, in the aggregate, or by the

private sector, of $100 million or more (adjusted annually for

inflation).

The agency believes that the revised rule is consistent with the

regulatory philosophy and principles identified in the Executive Order

and in these two statutes. The agency has determined that this rule is

a ``significant regulatory action'' as defined in section 3(f)(4) of

Executive Order 12866 because it raises novel policy issues. To the

extent that any of the standards and criteria entail costs to the DOD,

these standards and obligations are already assumed by DOD; they are

enunciated here to stress their importance to safeguarding the health

and welfare of military personnel to minimize the need to use this

rule. With respect to the Regulatory Flexibility Act (5 U.S.C. 605(b)),

any economic cost of the rule would be incurred only by DOD, which is

not a small entity. Therefore, the agency certifies that the rule will

not have significant economic impact on a substantial number of small

entities. Under the Regulatory Flexibility Act, therefore, no further

analysis is required. Similarly, because the rule does not impose any

mandates on State, local, or tribal governments, or the private sector

that will result in a 1-year expenditure of $100 million or more,

[[Page 54188]]

FDA is not required to perform a cost-benefit analysis under the

Unfunded Mandates Reform Act.

IX. Paperwork

This interim final rule contains no collections of information

subject to the Paperwork Reduction Act of 1995.

X. References

The following references have been placed on display in the Dockets

Management Branch (address above) and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday through Friday.

1. Letter from the Lead Deputy Commissioner, FDA, to the Acting

Deputy Secretary of Defense for Health Affairs, July 22, 1997.

2. Letter from the Army Surgeon General to the Lead Deputy

Commissioner, FDA, responding to the July 22, 1997, letter, October

23, 1997.

3. Letter from the Lead Deputy Commissioner, FDA, to the Acting

Deputy Secretary of Defense for Health Affairs, December 22, 1997.

4. Memorandum for record, minutes of the October 4, 1990,

ninety-third meeting of the U.S. Army Medical Research Institute of

Infectious Diseases Human Use Committee, October 5, 1990.

List of Subjects

21 CFR Part 50

Human research subjects, Prisoners, Reporting and recordkeeping

requirements, Safety.

21 CFR Part 312

Drugs, Exports, Imports, Investigations, Labeling, Medical

research, Reporting and recordkeeping requirements, Safety.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs, 21 CFR parts

50 and 312 are amended as follows:

PART 50--PROTECTION OF HUMAN SUBJECTS

1. The authority citation for 21 CFR part 50 continues to read as

follows:

Authority: 21 U.S.C. 321, 346, 346a, 348, 352, 353, 355, 360,

360c-360f, 360h-360j, 371, 379e, 381; 42 U.S.C. 216, 241, 262, 263b-

263n.

2. Section 50.23 is amended by revising paragraph (d) to read as

follows:

Sec. 50.23 Exception from general requirements.

* * * * *

(d)(1) Under 10 U.S.C. 1107(f) the President may waive the prior

consent requirement for the administration of an investigational new

drug to a member of the armed forces in connection with the member's

participation in a particular military operation. The statute specifies

that only the President may waive informed consent in this connection

and the President may grant such a waiver only if the President

determines in writing that obtaining consent: Is not feasible; is

contrary to the best interests of the military member; or is not in the

interests of national security. The statute further provides that in

making a determination to waive prior informed consent on the ground

that it is not feasible or the ground that it is contrary to the best

interests of the military members involved, the President shall apply

the standards and criteria that are set forth in the relevant FDA

regulations for a waiver of the prior informed consent requirements of

section 505(i)(4) of the Federal Food, Drug, and Cosmetic Act (21

U.S.C. 355(i)(4)). Before such a determination may be made that

obtaining informed consent from military personnel prior to the use of

an investigational drug (including an antibiotic or biological product)

in a specific protocol under an investigational new drug application

(IND) sponsored by the Department of Defense (DOD) and limited to

specific military personnel involved in a particular military operation

is not feasible or is contrary to the best interests of the military

members involved the Secretary of Defense must first request such a

determination from the President, and certify and document to the

President that the following standards and criteria contained in

paragraphs (d)(1) through (d)(4) of this section have been met.

(i) The extent and strength of evidence of the safety and

effectiveness of the investigational new drug in relation to the

medical risk that could be encountered during the military operation

supports the drug's administration under an IND.

(ii) The military operation presents a substantial risk that

military personnel may be subject to a chemical, biological, nuclear,

or other exposure likely to produce death or serious or life-

threatening injury or illness.

(iii) There is no available satisfactory alternative therapeutic

or preventive treatment in relation to the intended use of the

investigational new drug.

(iv) Conditioning use of the investigational new drug on the

voluntary participation of each member could significantly risk the

safety and health of any individual member who would decline its use,

the safety of other military personnel, and the accomplishment of the

military mission.

(v) A duly constituted institutional review board (IRB)

established and operated in accordance with the requirements of

paragraphs (d)(2) and (d)(3) of this section, responsible for review of

the study, has reviewed and approved the investigational new drug

protocol and the administration of the investigational new drug without

informed consent. DOD's request is to include the documentation

required by Sec. 56.115(a)(2) of this chapter.

(vi) DOD has explained:

(A) The context in which the investigational drug will be

administered, e.g., the setting or whether it will be self-administered

or it will be administered by a health professional;

(B) The nature of the disease or condition for which the

preventive or therapeutic treatment is intended; and

(C) To the extent there are existing data or information

available, information on conditions that could alter the effects of

the investigational drug.

(vii) DOD's recordkeeping system is capable of tracking and will

be used to track the proposed treatment from supplier to the individual

recipient.

(viii) Each member involved in the military operation will be

given, prior to the administration of the investigational new drug, a

specific written information sheet (including information required by

10 U.S.C. 1107(d)) concerning the investigational new drug, the risks

and benefits of its use, potential side effects, and other pertinent

information about the appropriate use of the product.

(ix) Medical records of members involved in the military operation

will accurately document the receipt by members of the notification

required by paragraph (d)(1)(viii) of this section.

(x) Medical records of members involved in the military operation

will accurately document the receipt by members of any investigational

new drugs in accordance with FDA regulations including part 312 of this

chapter.

(xi) DOD will provide adequate followup to assess whether there

are beneficial or adverse health consequences that result from the use

of the investigational product.

(xii) DOD is pursuing drug development, including a time line, and

marketing approval with due diligence.

(xiii) FDA has concluded that the investigational new drug

protocol may proceed subject to a decision by the President on the

informed consent waiver request.

(xiv) DOD will provide training to the appropriate medical

personnel and potential recipients on the specific

[[Page 54189]]

investigational new drug to be administered prior to its use.

(xv) DOD has stated and justified the time period for which the

waiver is needed, not to exceed one year, unless separately renewed

under these standards and criteria.

(xvi) DOD shall have a continuing obligation to report to the FDA

and to the President any changed circumstances relating to these

standards and criteria (including the time period referred to in

paragraph (d)(1)(xv) of this section) or that otherwise might affect

the determination to use an investigational new drug without informed

consent.

(xvii) DOD is to provide public notice as soon as practicable and

consistent with classification requirements through notice in the

Federal Register describing each waiver of informed consent

determination, a summary of the most updated scientific information on

the products used, and other pertinent information.

(xviii) Use of the investigational drug without informed consent

otherwise conforms with applicable law.

(2) The duly constituted institutional review board, described in

paragraph (d)(1)(v) of this section, must include at least 3

nonaffiliated members who shall not be employees or officers of the

Federal Government (other than for purposes of membership on the IRB)

and shall be required to obtain any necessary security clearances. This

IRB shall review the proposed IND protocol at a convened meeting at

which a majority of the members are present including at least one

member whose primary concerns are in nonscientific areas and, if

feasible, including a majority of the nonaffiliated members. The

information required by Sec. 56.115(a)(2) of this chapter is to be

provided to the Secretary of Defense for further review.

(3) The duly constituted institutional review board, described in

paragraph (d)(1)(v) of this section, must review and approve:

(i) The required information sheet;

(ii) The adequacy of the plan to disseminate information,

including distribution of the information sheet to potential

recipients, on the investigational product (e.g., in forms other than

written);

(iii) The adequacy of the information and plans for its

dissemination to health care providers, including potential side

effects, contraindications, potential interactions, and other pertinent

considerations; and

(iv) An informed consent form as required by part 50 of this

chapter, in those circumstances in which DOD determines that informed

consent may be obtained from some or all personnel involved.

(4) DOD is to submit to FDA summaries of institutional review

board meetings at which the proposed protocol has been reviewed.

(5) Nothing in these criteria or standards is intended to preempt

or limit FDA's and DOD's authority or obligations under applicable

statutes and regulations.

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

3. The authority citation for 21 CFR part 312 is revised to read as

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371; 42

U.S.C. 262.

4. Section 312.42 is amended by adding paragraph (b)(6) to read as

follows:

Sec. 312.42 Clinical holds and requests for modification.

* * * * *

(b) * * *

(6) Clinical hold of any investigation involving an exception from

informed consent under Sec. 50.23(d) of this chapter. FDA may place a

proposed or ongoing investigation involving an exception from informed

consent under Sec. 50.23(d) of this chapter on clinical hold if it is

determined that:

(i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this

section apply; or

(ii) A determination by the President to waive the prior consent

requirement for the administration of an investigational new drug has

not been made.

* * * * *

Dated: May 25, 1999.

Jane E. Henney,

Commissioner of Food and Drugs.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 99-25376 Filed 10-4-99; 8:45 am]

BILLING CODE 4160-01-F