Protection of Human Subjects; Informed Consent

SUMMARY: The Food and Drug Administration (FDA) is amending its current

informed consent regulations to permit harmonization of the Department

of Health and Human Services' (DHHS) policies on emergency research and

to reduce confusion on when such research can proceed without obtaining

an individual subject's informed consent. This regulation provides a

narrow exception to the requirement for obtaining and documenting

informed consent from each human subject, or his or her legally

authorized representative, prior to initiation of an experimental

intervention. The exception would apply to a limited class of research

activities involving human subjects who are in need of emergency

medical intervention but who cannot give informed consent because of

their life-threatening medical condition, and who do not have a legally

authorized person to represent them. FDA is taking this action in

response to growing concerns that current rules are making high quality

acute care research activities difficult or impossible to carry out at

a time when the need for such research is increasingly recognized.

EFFECTIVE DATE: These regulations are effective November 1, 1996.

FOR FURTHER INFORMATION CONTACT: Glen D. Drew, Office of Health Affairs

(HFY-20), Food and Drug Administration, Rockville, MD 20852, 301-443-

1382.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of September 21, 1995 (60 FR 49086), the

Secretary of Health and Human Services and the Commissioner of Food and

Drugs proposed to amend FDA's current informed consent regulations to

permit emergency care research. FDA proposed this action in response to

growing concerns that current rules are making high quality acute care

research activities difficult or impossible to carry out at a time when

the need for such research is increasingly recognized. By permitting

certain adequate and well-controlled clinical trials to occur that

involve human subjects who are confronted by a life-threatening

situation and who also are unable to give informed consent because of

their medical condition, the agency expects the clinical trials to

allow individuals in these situations access to potentially life-saving

therapies and to result in advancement in knowledge and improvement of

therapies used in emergency medical situations that currently have poor

clinical outcome.

FDA allowed 45 days for comment on the proposal of September 21,

1995. Written comments received in response to the proposal are on file

in the Dockets Management Branch. Comments were received from clinical

investigators, institutional review boards, patient advocacy groups,

trade associations, professional societies, drug and medical device

companies, and private citizens. The substantive comments received and

FDA's responses are discussed below.

Approximately 90 comments were received on the proposed rule. The

vast majority of these comments supported the proposal, although many

of these comments contained suggestions or requests for clarification.

A number of the comments that supported the proposal came from

organizations and associations representing large numbers of members.

These included the Brain Injury Association, the National Stroke

Association, the American Academy of Orthopaedic Surgeons, the

Coalition of Acute Resuscitation and Critical Care Researchers, Applied

Research Ethics National Association, Pharmaceutical Research and

Manufacturers of America, Health Industry Manufacturers Association

(HIMA), the American Academy of Pediatrics, the American Heart

Association Emergency Cardiac Care Committee, the American College of

Emergency Physicians, the American Medical Association, the American

College of Cardiology, the Society of Critical Care Medicine, the

National Association of EMS Physicians, the American College of

Obstetricians and Gynecology, and the American College of Physicians.

A number of the comments in favor of the proposal cited how it will

facilitate research in this patient population, provide the necessary

safeguards to ensure responsible and ethical research with protection

of the human subjects, and ultimately speed the wide availability of

products proven efficacious to individuals in life-threatening

situations. For example, the American College of Physicians and the

Project on Informed Consent of the University of Pennsylvania Center

for Bioethics commented that they ``applaud these proposed regulations

as a much needed step in the advancement of vital emergency research

with careful attention to the rights and welfare of human research

subjects.'' The American Heart Association commented that ``We are

particularly pleased with the balance that appears to have been struck

between the need for conducting high quality clinical research in an

effort to develop better treatments for critically ill patients and the

protection of human subjects.'' The American Medical Association

commented that ``The proposed rules are far superior to their

inadequate antecedents in balancing the need for emergency research

with respect for the paramount concern for patient safety, welfare and

comfort.'' The Brain Injury Association commented that ``* * * this

rule is a major step towards increasing the available therapies and

medical care available for those individuals who are critically ill or

injured.'' The Coalition of Acute Resuscitation and Critical Care

Researchers commented that ``* * * this proposed rule is a significant

step forward towards advancing the medical care of critically ill or

injured patients for whom current therapies are unsatisfactory or

unproven.'' The National Stoke Association commented that ``* * * once

in practice it will help to appropriately expedite study enrollments

thus allowing for earlier study completion, analysis, and ultimately

will speed the availability of those drugs proven efficacious to the

one-half million people who suffer stroke each year.''

These comments are addressed in more detail in sections II and III

of this document.

Generally, the 16 comments opposed to the proposed rule were from

individuals who were not convinced by the agency's description of the

legal and ethical basis for the rule, and these comments concluded that

informed consent should not be waived under any circumstances. Some of

these comments suggested that the agency was proceeding hastily and

under undue pressure from the research community. In section II of this

document, we address the general comments first, followed by the more

specific comments.

II. General Comments

A. Need for the Rule

1. One comment questioned the need for the rule and whether there

were hard data documenting the number of

[[Page 51499]]

subjects eligible for these types of research activities who are lost

to enrollment due to an inability to obtain informed consent from the

subject or the subject's authorized representative. Another comment

questioned the need for this rule based on the DHHS waiver granted in

July 1995 for a hypothermia study, arguing that: (1) The waiver was not

needed to complete a reasonable preliminary sample, (2) the criteria

for participation were needlessly inclusive, (3) the investigator used

questionable tactics to achieve waiver, (4) the provisions for

oversight were inadequate, and (5) the provisions for monitoring were

inadequate. This comment went on to discuss ``the overarching

considerations'' for the rule, arguing that it is not in the subject's

interest to prevent death in order to linger in a vegetative state;

that the high percentage of families agreeing to continuing

participation in the research after the fact demonstrates how ill-

informed they are about the possibility of negative outcomes, e.g.,

prolonged vegetative state, dissipation of financial resources, court

challenges to terminate life support; that subjects will be misenrolled

in ``an abundance'' of life-threatening situations; that the rule does

not address or provide for followup or special circumstances for

terminating life support for ``saved'' individuals in these studies;

and that it is not clear who will bear the cost and burden to sustain

an individual who has been ``saved'' from a life-threatening medical

condition by being on a research study.

The preamble to the proposed rule extensively discussed why this

rule is needed and why this limited class of research has been unable

to proceed under existing requirements. The purpose of this rule is to

permit the study of potential improvements in the treatment of life-

threatening conditions where current treatment is unproven or

unsatisfactory, in order to improve interventions and patient outcomes.

It is not the goal of this rule to leave study subjects in vegetative

states or to have any of the other negative outcomes outlined in the

comments. The risks to patients of having these negative outcomes exist

now with interventions that are unproven or unsatisfactory. If

interventions are improved, patient outcomes will be improved. The

possibility of worsened outcome or adverse reactions will be assessed

before the clinical investigation begins by the IRB and during the

investigation by the data monitoring committee that is required under

the regulation. The regulations require the institutional review board

(IRB) to ensure that risks to subjects are minimized and to determine

that risks to subjects are reasonable in relation to anticipated

benefits to subjects (see Sec. 56.111(a)(1) and (a)(2) (21 CFR

56.111(a)(1) and (a)(2)), respectively). The rule does not address the

issue of terminating life support because this is dictated by State law

and is implemented through such standard procedures as ``do not

resuscitate'' orders.

B. Ethical Objections to the Rule

2. Several objections to the proposed rule noted that the major

protection from research risks remains informed consent and that

without this procedure, potential abuse of research subjects will

always remain unacceptably high; that it is unethical for patients who

cannot consent to receive nonstandard care; that overriding individual

autonomy and not obtaining informed consent is unacceptable; that

therapeutic intent is not sufficient to obviate consent when there are

no data or when there is uncertainty or disagreement. Some of these

comments mentioned the recent report of the President's Advisory

Committee on Human Radiation Experiments, in which radiation

experiments without the subjects' consent are condemned as a wrongful

use of persons as means to the ends of others; others mentioned

examples from Nazi Germany, Stalin's U.S.S.R. and other totalitarian

regimes. Some of these comments noted that it is particularly

objectionable that there is no way to avoid involvement as a subject in

this research if, as an individual, one objects to the research.

The agency acknowledges that the waiver of informed consent is a

serious matter. That is why it has developed a regulation that requires

additional protections when informed consent is waived. The purpose of

this rule is to ensure such protections.

The National Commission for the Protection of Human Subjects of

Biomedical and Behavioral Research states in The Belmont Report that:

Respect for persons incorporates at least two basic ethical

convictions: first, that individuals should be treated as autonomous

agents, and second, that persons with diminished autonomy are

entitled to protection. The principle of respect for persons thus

divides into two separate moral requirements: the requirement to

acknowledge autonomy and the requirement to protect those with

diminished autonomy.

This rule, Sec. 50.24 (21 CFR 50.24) in part 50 (21 CFR part 50), can

be invoked for emergency research in which it is not feasible to obtain

informed consent from prospective subjects. As such, these subjects

have diminished autonomy and are entitled to protection. The Belmont

Report states that:

The extent of protection afforded [to individuals with

diminished autonomy] should depend upon the risk of harm and the

likelihood of benefit. The judgment that any individual lacks

autonomy should be periodically reevaluated and will vary in

different situations.

The Belmont Report, thus, states that: (1) Subjects with diminished

autonomy are entitled to protection; (2) the extent of protection

should depend upon the risk of harm and the likelihood of benefit; and

(3) the judgment that any individual lacks autonomy should be

periodically reevaluated. This regulation incorporates each of these

principles.

The regulation recognizes that subjects with diminished autonomy

are entitled to protection. These additional protections include the

requirements in the regulation for consultation with representatives of

the communities from which the subjects will be drawn; public

disclosure of the clinical investigation and its risks and expected

benefits prior to initiation of the investigation; public disclosure of

sufficient information following completion of the investigation to

apprise the community and researchers of the results of the

investigation; the establishment of a data monitoring committee to

exercise oversight of the investigation; and, if consent is not

feasible and a legally authorized representative is not available,

providing an opportunity for a family member to object to a subject's

participation in the investigation, if feasible within the therapeutic

window.

The regulation recognizes that the extent of protection should

depend upon the risk of harm and the likelihood of benefit to the

subjects. The regulation requires the IRB to find and document that

appropriate animal and other preclinical studies have been conducted;

that the information derived from those studies and related evidence

support the potential of providing a direct benefit to the individual

subjects; and that the risks associated with the investigation are

reasonable in the light of what is known about the prospective

subjects' medical condition, the risks and benefits of standard

therapy, if any, and what is known about the risks and benefits of the

proposed intervention or activity.

The regulation recognizes that the judgment that any individual

lacks autonomy should be periodically reevaluated. This is reflected in

two requirements: (1) The IRB must review and approve informed consent

[[Page 51500]]

procedures and an informed consent document for use with subjects or

their legal representatives in situations where use of such procedures

and documents is feasible; and (2) at the earliest feasible

opportunity, each subject (or a legally authorized representative or

family member) will be informed of the subject's inclusion in the

research, the details of the research, and that the subject (or

representative or family member) may discontinue the subject's

participation at any time without penalty or loss of benefits to which

the subject is otherwise entitled.

In response to the comments that expressed concern about the

ability of an individual to avoid involvement as a subject in this

research, the agency thinks that the opportunity for individuals to

express objections to the research may be optimized in a number of

ways. Comments suggested making available medical bracelets that record

refusal to participate in the research, and publicizing the existence

of the bracelets; and excluding from participation those individuals

with advance directives rejecting such research (most feasible for

hospitalized patients). The agency encourages IRB's, investigators, and

sponsors to work together to maximize the ability of individuals to

prevent their inclusion in research to which they would object. The

agency does not believe that this rule creates a situation that differs

significantly from other emergency situations warranting intervention

in that individuals in life-threatening situations are often unable to

direct decisions concerning their health care and are, therefore,

unable to consent or object to a particular treatment. Yet they are

routinely treated by State-licensed medical practitioners. This

inability to exercise autonomy is not unique to the subjects who will

be eligible for this research--it is common to the majority of

individuals who may be in these life-threatening situations.

FDA thinks that the protections contained in this rule including

IRB review, the requirements for obtaining informed consent when it is

feasible, and for community consultation and disclosure will prevent

unethical research from occurring.

FDA expects these procedures involving waiver of informed consent

to be used infrequently. As noted, the research carried out under such

a waiver must present the potential of direct benefit to the individual

subjects. It should be initiated only after appropriate animal and

other preclinical studies have been conducted, and it is clear that the

information derived from those studies and related evidence support the

potential of direct benefit to the individual subjects.

3. One comment stated that the proposal violates the American

Hospital Association's ``Patient's Bill of Rights'' to fully informed

consent.

The agency has reviewed the AHA's Patient's Bill of Rights and

concludes that there is no conflict between this rule and that

document. In particular, the agency notes that the Patient's Bill of

Rights recognizes that an exception occurs ``in emergencies when the

patient lacks decision-making capacity and the need for treatment is

urgent.''

4. Another comment questioned the agency's discussion of respect

for persons in the preamble to the proposal and the agency's supposed

conclusion that if individuals capable of exercising their autonomy

refuse to enroll in research, this justifies diminished protection to

those individuals who lack the capacity for autonomous choice. This

comment defined the informed consent doctrine as: (1) Promoting

individual autonomy; (2) respecting human dignity; (3) encouraging

professional self-scrutiny; (4) promoting rational decisionmaking; (5)

avoiding deceit and coercion; and (6) educating the public. It then

concluded, that by exempting emergency research from informed consent,

the agency was concluding that these values have no relevance to

decisions made in the context of emergency research.

This comment misrepresents the agency's discussion of the principle

of respect for persons. In the preamble to the proposed rule, the

agency described:

[H]ow the principle of respect for persons incorporates two

general rules of ethical behavior: (1) Competent individuals must be

treated as autonomous agents * * *; and (2) persons whose autonomy

is absent or diminished may participate in research only if

additional protections are provided for them.

(60 FR 49086 at 49093, September 21, 1995)

This rule, in fact, incorporates the values described in the comment to

the extent that they are relevant to decisions made in the context of

emergency research.

5. A number of comments misinterpreted the agency's description of

the principle of justice in the preamble to the proposed rule, and were

offended by the idea that it is acceptable for a researcher to waive

consent because if consent were requested, it would be refused. One

comment suggested that the agency clarify that it meant that it is

often easier to locate legal representatives from white populations

than from minority populations, and for that reason if consent were

required from a legally authorized representative, the requirement

could prevent equitable numbers of minority patients from having the

opportunity to participate in emergency research. The Indian Health

Service recommended that the agency supplement its discussion of

justice by adding the following:

Waiving informed consent will increase justice only in

communities or sub-communities with a low percentage of people who

would refuse to participate if asked. Many minority or economically

disadvantaged communities distrust research more, and have higher

percentages of refusers, than white middle class communities; in

such communities, the ethical principle of justice would favor

maximizing self-determination (i.e., informed consent) over

achieving high rates of participation. Justice would also require

the public disclosure to and consultation with those communities as

required in the Proposed Rule; if those communities do not agree to

be sites, consideration should be given to doing the research

elsewhere.

The Indian Health Service, in supporting the intent of the rule,

articulated two aspects of the problem: (1) Finding legally qualified

surrogates for individuals who lack telephones, for example, which is a

socioeconomic barrier; and (2) a surrogate's unwillingness to enroll a

relative in the research, based on distrust of research and

researchers. If certain communities have a higher prevalence of

refusers than others, the ethical harm of inadvertently enrolling

people in research against their will would fall on those communities

with a higher prevalence of refusers. Thus, the Indian Health Service

(IHS) concluded that while it may be appropriate to waive informed

consent based on socioeconomic barriers, it is not appropriate to waive

informed consent in communities in which there are lower rates of

obtaining surrogate consent due to the unwillingness of surrogates,

i.e., high refusal rates. Another comment noted that if the community

in which an emergency research study is carried out has a large

minority and lower income population, then the likelihood of the

community agreeing prospectively to participate in the study would be

small or nonexistent; ethically this would violate the principle of

justice in that such communities would be unlikely to share the burdens

and benefits of participation in such research.

The agency's comments concerning justice, in the preamble to the

proposed rule, concerned the ability of health care delivery personnel

to locate legally authorized representatives. The agency agrees with

the IHS articulation of the

[[Page 51501]]

two aspects of the problem. The agency would not consider writing a

rule that would permit the waiver of informed consent in a situation

where if consent were requested, it would be refused. Such an action

would violate ethical principles.

The agency has implicitly addressed the problem of a surrogate's

unwillingness to enroll a relative in research through the rule's

requirement for community involvement, including consultation with and

disclosure to the community, and by providing that consent from the

subject or the subject's legally authorized representative be obtained

or an opportunity for a family member to object be provided when it is

feasible.

If an IRB decides that its community should not participate in

research, the agency does not believe that decision would violate the

principle of justice. Justice, in this context, requires only that the

community have the opportunity to participate in the research if asked.

C. Harmonization

6. A number of comments applauded the intent of FDA and DHHS to

harmonize regulations in this area. Concern was expressed, however,

that because FDA and DHHS did not propose regulations simultaneously,

the two regulations may not ultimately be identical, thus thwarting a

major objective of this endeavor. One comment expressed concern that

the DHHS waiver might follow the specific project waiver for

hypothermia research that was published in July 1995, that, according

to the comment, was not sufficiently protective of subject rights.

Another comment suggested that for studies that do not involve drugs or

devices, DHHS develop an analogous mechanism to FDA's requirement that

studies be submitted for agency review. Another comment suggested that

the two sets of regulations not be in total harmony in this regard,

because a greater degree of protection of subjects is necessary for

studies of drugs and devices that are not yet FDA-approved, than for

those involving drugs or devices that have received approval. One

comment encouraged FDA and the Office for Protection from Research

Risks (OPRR) to work together to ensure that current Multiple Project

Assurances remain valid and not require renegotiation as a result of

this rule.

DHHS has committed to consistency between the FDA final rule and

the Secretarial waiver of the DHHS regulations in all critical

respects. Elsewhere in this issue of the Federal Register is the

Secretarial waiver of the DHHS regulations for the protection of

research subjects for emergency research. The agency notes that FDA's

rule requires investigational new drug applications (IND's) and

investigational device exemptions (IDE's) for all clinical

investigations involving drugs and devices seeking an exception to the

requirement for informed consent, including both those that have

received marketing approval and those that have not.

7. Other comments asked for clarification as to whether the

requirement contained in Sec. 50.24(d) would apply to studies that

attempt to elucidate a pathophysiologic explanation (e.g., blood

drawing studies); studies that use interventions of different

techniques (e.g., two different methods of bystander CPR); research

designed to explore basic pathophysiological mechanisms in emergency

situations; studies to compare the timing of standard fluid

administration for shock and surgical techniques; etc. If FDA's

regulation did not apply, these comments asked if the DHHS

``harmonized'' regulation would apply to these studies and require

prior DHHS review or whether some other agency would be responsible for

prior review of the proposed research.

These regulations are applicable only to clinical investigations

involving products that are regulated by FDA. The DHHS regulations

apply to research supported or conducted by the Department or conducted

in an institution that has agreed to review all research, regardless of

its funding source, in accord with the DHHS regulations. The

``harmonized'' regulations have compatible criteria; their basic

requirements are in agreement. FDA includes terms specific to the type

of research covered by FDA regulations (e.g., it uses the term clinical

investigation instead of research). Both the DHHS and FDA recognize

that there may be research that is neither regulated by FDA nor

supported or conducted by DHHS; for that research, it is possible that

neither regulation will apply.

D. Comment Period and Effective Date

Several comments opposed to the regulation objected to the 45-day

comment period and the agency's proposal that the final rule will be

effective upon publication.

8. One comment suggested that the effective date of the regulations

should be 30 days after publication of the final rule. This comment

noted that this research has been halted since mid-1993, that all

parties will need time to develop adequate policies and procedures to

comply with the new rule, and that distribution of the policy to those

affected will take up to 30 days.

The agency agrees with this comment and has made the effective date

of the final rule 30 days after its publication in the Federal

Register. The agency notes that the Secretarial waiver of the DHHS

regulations, published elsewhere in this Federal Register, is also

effective 30 days after its publication. IND's and IDE's that intend to

invoke this rule may be submitted to the agency on or after its

publication date and should include a description of how the clinical

investigation proposes to meet the conditions of this regulation. These

investigations cannot begin until the rule is effective, the agency has

reviewed the investigation against the requirements contained in this

final rule, a letter has issued to the sponsor advising the sponsor

that the investigation may proceed, the investigation has been reviewed

and approved by an IRB, and the community consultation and disclosure

required by this rule have occurred.

9. Comments objecting to the 45-day comment period suggested that

there was inadequate time to discuss the proposed changes in the

regulation at length with a broader audience, that the IRB community is

ill-informed about the proposed rule change and therefore the comment

period should be extended, the issue revisited, and the rule

reconsidered. One of these comments stated that the process leading to

development of the rule was flawed and that it appears that the comment

period is irrelevant, that no significant review of the basic issues

will occur, and, thus, the rule is a fait accompli.

As described in detail in the preamble to the proposed rule, the

issues associated with this rule were debated at length at conferences,

during FDA and NIH cosponsored Public Forum on Informed Consent in

Clinical Research Conducted in Emergency Circumstances, at a

congressional hearing, and in various articles. The agency received no

formal request for a general extension of the comment period; instead,

it received numerous thoughtful comments and has modified the proposed

rule as a result of those comments. 21 CFR 10.40(b)(2) states that a

proposed rule ``* * * will provide 60 days for comment, although the

Commissioner may shorten or lengthen this time period for good cause.

In no event is the time for comment to be less than 10 days.'' In the

proposed rule, the agency explained why the Commissioner determined

that there was good cause to shorten the comment period from 60 to 45

days.

[[Page 51502]]

In order to encourage comments on this rule, the agency conducted a

number of out-reach efforts to publicize publication of the proposal.

The agency provided information on the proposed rule to national media

and trade press contacts. The agency mailed copies of the proposal to

all registrants at the January 1995 Public Forum on Informed Consent in

Clinical Research Conducted in Emergency Circumstances and to over

1,000 IRB's and over 250 health professional organizations and consumer

groups. FDA also distributed copies at workshops and at national

meetings of IRB organizations. The agency invited consumer, health

professional, and industry organizations to briefing meetings where the

proposal was described and questions could be answered. The agency

encouraged the submission of comments to the administrative record

maintained by the Dockets Management Branch whenever possible.

E. Preemptive Effect

10. In the preamble to the proposed rule, FDA requested comment on

the need to preempt local and State regulations. The agency received a

number of comments both for and against the need for preemption.

Comments received that were opposed to preemption included the

following: There is no legitimate (constitutional) over-riding Federal

concern that requires the Federal Government to preempt local and State

requirements; it is inappropriate to remove the ability of citizens to

enact State and/or local laws that would require additional protections

for research subjects, or to restrict the conduct of this type of

research if citizens find it objectionable based on community

standards; it is not logical to prohibit local action when the

regulation itself emphasizes community involvement and deference to

community standards.

The IHS objected to Federal preemption because it would: (1)

Counter the long-standing Federal policy not to place restrictions on

tribal sovereignty; (2) be an unnecessary limitation, because retaining

tribal sovereignty would have no measurable adverse effect on the

nation or on emergency research as a whole; (3) give American Indian

and Alaska Native (AI/AN) people and governments one more reason to

distrust the Federal Government, because they would see the rule as

putting AI/AN people at risk for the good of non-AI/AN people and

communities; and give AI/AN people and governments one more reason to

distrust research, because they would see the rule as overriding a

patient's or family's desire not to participate in research--a desire

more common in AI/AN communities than in white middle class

communities.

Other comments noted that the proposal did not recognize tribal

sovereignty and that it undermines the tribal government's authority to

implement stricter requirements for biomedical research conducted on

persons residing in tribal jurisdictional boundaries. Comments noted

that the tribal review process is in place to protect tribal members

from unnecessary or undesirable research.

Another comment opposed to preemption noted that the rule would

preempt State and local laws for the minimum protections acceptable for

emergency research involving waiver of informed consent; however,

without preemption, it permits greater protections to be imposed at the

State or local levels. One comment suggested that in lieu of

preemption, FDA and IRB's should track how States, local, or tribal

governments retain or amend their laws in response to public discussion

by researchers with those governments and assess the various reactions

after 3 years.

Other comments supported the need for preemption in order to ensure

national uniformity; to prevent or limit liability of universities,

hospitals, IRB members, clinical investigators, and sponsors for

failure to provide informed consent under State law or in the event of

a poor subject outcome; and to enhance the ability to conduct valuable

research with critically ill subjects. These comments stated that the

subject protections included in the proposed regulation are substantial

enough to justify Federal preemption of State and local law, and that

current State laws (e.g., in the State of Florida) would preclude

research that otherwise could be authorized by IRB's under these rules.

Several comments supported the need for preemption, noting the

difficulty caused by differing State laws that define who may serve as

a legal representative or that are ambiguous on this issue. Another

comment noted that without Federal preemption, Federal uniformity in

the application of waiver of informed consent in a specific setting

will not occur. This comment argued that Federal preemption would: (1)

Forestall wasteful State court litigation to explore whether the scope

of the privilege of emergency action without consent is consistent with

the proposed Federal rule, and any related potential liability; and (2)

implement congressional intent to create nationally uniform criteria

for informed consent and research involving human subjects.

The Coalition of Acute Resuscitation and Critical Care Researchers

surveyed a number of State representatives regarding State regulations

for informed consent for research and identification of surrogates. The

results of that survey (with 19 States represented) indicate that there

are very few States that have specific legal requirements pertaining to

waiver of consent for research.

The agency has carefully considered each of these arguments in

support of, and opposed to, preemption of State law. The agency has

concluded that it would be inappropriate to preempt State law at this

time. Preemption of State law would prevent the application of State or

local law that requires additional protections to research subjects

and, as such, would be inconsistent with the existing Federal policy

for the Protection of Human Subjects and the DHHS regulations (45 CFR

46); in addition, it would be inconsistent with the notion of community

norms, upon which this regulation is based.

F. Followup/Reassessment

11. One comment recommended that the implementation of this rule be

assessed in 3 years and that any pending questions be addressed during

the assessment. Another comment asked the agency to announce its intent

to survey and analyze the experience with the rule following 3 years of

implementation. The comment recommended that the rule encourage IRB's

and researchers to track implementation information including: The

number of times the researcher was able to contact legally authorized

representatives within the allowed therapeutic window time period;

problems with the documentation and procedures used for the consent

process with those representatives; the percentage of subjects or

legally authorized representatives who wanted to discontinue the

intervention or to remove their data from the research database in the

posthoc debriefing; problems with documents and procedures used to give

the community the preresearch public information and the post-research

information; and problems with the documents and procedures for

consulting with community representatives. This comment suggested that

this information be described both as seen by the IRB and by the

experienced researcher.

The agency agrees that it will be important to assess

implementation of this rule and, thus, the agency intends to evaluate

implementation of this rule

[[Page 51503]]

on an ongoing basis. The agency believes that a sponsor's IND or IDE

and new drug application (NDA), product license application (PLA), or

premarket approval application (PMA) should contain sufficient

information under the agency's existing reporting and recordkeeping

requirements for the agency to assess how well this rule is working

without requiring additional information collection and recordkeeping

by researchers and IRB's of their experiences under the rule. The

agency, however, encourages IRB's, researchers, and sponsors to share

their experiences under this rule, for example, in publications and at

conferences, so that the research community and public can benefit from

their experiences. The agency notes that for research that is regulated

by FDA, although subjects, legally authorized representatives, or

family members may elect to withdraw from continued participation in

the clinical investigation, they may not remove previously collected

data from the research database because it is critical that FDA obtain

and be able to consider all data on a product's use in order to be able

to determine its safety and efficacy.

G. Scope/Applicability

1. Special Populations

12. One comment questioned the applicability of this rule to

specific special patient populations. This comment recommended that FDA

rule state that it does not apply to research involving prisoners or

fetuses; and urged that the decision about its applicability to

emergency research targeting pregnant women be made after the DHHS

regulations have been revised and the 3 year period in which experience

of implementing the rule will be obtained and analyzed. This comment

recommended that pregnant women should not be excluded from emergency

research. This comment also recommended that the rule state that it

does not apply to children now; rules for pediatric emergency research

should be developed by the end of the 3 year period of experience and

assessment; and noted that the process of Secretarial waiver is

available if an exception for a specific pediatric emergency protocol

must be made before then.

Taking a contrary view, the American Academy of Pediatrics stated

that:

* * * it is important that children be included in research

protocols, including those on emergency treatments, so that the

safety and efficacy of various treatment methods can be determined

in a scientific manner. We believe that this proposed regulation

will help to further that objective while protecting children as

much as possible by requiring that a consent document be available

in cases where surrogate permission can be obtained in a timely

manner.

The agency believes that it would be inappropriate to exclude any

special subject population from this regulation. Moreover, for research

regulated by FDA, a Secretarial waiver of the informed consent

requirement may not be an option. Thus, the agency is not limiting the

applicability of this regulation to exclude any special subject

population. The agency notes that it is the general responsibility of

the IRB, where some or all of the subjects are likely to be vulnerable

to coercion or undue influence, to ensure that appropriate additional

safeguards have been included in the clinical investigation to protect

the rights and welfare of these subjects. (See 21 CFR 56.111(b).) The

subject population covered in this rule is, in a sense, a particularly

vulnerable population, by having no capacity to decide about medical

treatments. The additional safeguards in the rule are included for this

reason.

2. Existing Regulations

13. One comment asked the agency and DHHS, respectively, to

explicitly state, when this rule is finalized, that FDA will retain

Sec. 50.23(a) (21 CFR 50.23(a)) and the DHHS will retain 45 CFR

46.116(d).

Both FDA and DHHS will retain these sections in the Code of Federal

Regulations. These sections will continue to be useful in situations

not otherwise covered by this regulation.

14. Another comment suggested that the regulations address

compensation or medical treatment available in the event of

unanticipated injuries or death.

The agency agrees that it is important for all subjects in a

clinical investigation to be provided with the basic information

required by Sec. 50.25, including Sec. 50.25(a)(6) that requires that

information be provided to each subject about whether any compensation

and any medical treatments are available if injury occurs and, if so,

what they consist of, or where further information may be obtained. As

a result, the agency has modified Sec. 50.24(a)(6), previously numbered

Sec. 50.24(a)(5), to make it clear that the IRB-approved informed

consent document must be consistent with Sec. 50.25. The agency has

also modified Sec. 50.24(b) to make it clear that when prospective

informed consent cannot be obtained, the subject, or the subject's

legally authorized representative or family member is to be informed,

at the earliest feasible opportunity, of the subject's inclusion in the

clinical investigation, the details of the investigation, and other

information contained in the informed consent document.

15. A third comment requested the agency to retain two protections

previously established by the agency that are not contained in the

proposed rule: (1) That the intervention be in the health interest of

the subjects; and (2) that an attempt to obtain informed consent be

made and documented for enrolled research subjects by a physician

unaffiliated with the research activity.

The agency thinks that the concerns expressed by the first

protection are addressed in Sec. 50.24(a)(3), which requires that

participation in the research hold out the prospect of direct benefit

to the subjects. The second protection is similar to that contained in

Sec. 50.23(a), which requires, in effect, a second opinion from a

physician who is not otherwise participating in the clinical

investigation that the conditions for waiving informed consent are met.

This protection is performed for the class of subjects in this research

by the requirement in Sec. 50.24(a)(2) that a determination be made

that obtaining informed consent is not feasible and that this

determination receive the concurrence of a licensed physician who is

either an IRB member or a consultant to the IRB, and who is not

otherwise participating in the clinical investigation (Sec. 50.24(a)).

The agency notes that Sec. 50.24(b) requires that at the earliest

feasible opportunity, each subject is to be informed of the subject's

inclusion in the clinical investigation, the details of the

investigation and other information contained in the informed consent

document. The agency also notes that under new Sec. 50.24(a)(5), the

researcher is required to describe the efforts made to obtain informed

consent and make this information available to the IRB at the time of

continuing review.

3. Foreign Data

16. One comment noted that the rule was silent as to its potential

impact on the acceptability of data generated in emergency research

studies that are not subject to the proposed rule--i.e., studies

conducted outside the United States and outside the scope of the IND

and IDE regulations. This comment asked FDA to make it clear that such

studies will continue to be considered acceptable in terms of providing

evidence of safety and effectiveness and could be treated as pivotal

trials, even though they may not meet some of the proposed requirements

for the conduct

[[Page 51504]]

of emergency research. This comment stated that if this clarification

is not consistent with the agency's intent, then the proposal

effectively establishes a new, inappropriate standard concerning the

adequacy of clinical studies for purposes of providing evidence of

safety and effectiveness that would require specific notice-and-comment

rulemaking.

Sections 312.120 and 814.15 (21 CFR 312.120 and 814.15) describe

the criteria for acceptance by FDA of foreign clinical investigations

not conducted under an IND and IDE, respectively. In general, FDA

accepts such clinical investigations provided they are well designed,

well conducted, performed by qualified investigators, and conducted in

accordance with ethical principles acceptable to the world community.

FDA will accept such emergency research investigations provided that

they meet the requirements of Sec. 312.120 and Sec. 814.15. This rule

does not change the requirements of Sec. 312.120 and Sec. 814.15.

17. One comment noted that the International Conference on

Harmonisation Draft Guideline on Good Clinical Practice (GCP) (60 FR

42948, August 17, 1995) states that ``the rights, safety, and well-

being of the trial subjects are the most important considerations and

should prevail over [the] interests of science and society.'' This

comment suggested that the main argument for the proposed rule is for

the benefit that the new drugs and devices will bring to science and

society, rather then recognizing, as the GCP does, the value of the

individual and subject rights.

The agency disagrees that this rule is inconsistent with the ICH

Draft Guideline and has emphasized in the preamble to this regulation

that the basic rationale for this rule is that it holds out the

prospect of direct benefit to the subjects. The agency is committed to

protecting the rights of research subjects. In addition, FDA recognizes

that this rule may also serve society by making available more drugs

and devices for use in emergency, life-threatening situations. The

agency notes that the draft GCP cited specifically acknowledges the

need for waivers of informed consent in some circumstances.

4. Independent IRB's

18. One comment expressed concern about FDA's continued acceptance

of reviews by ``independent'' IRB's. This comment questioned the

ability of a nonlocal, independent IRB to have local insight and

knowledge necessary for comprehensive review and continuing oversight,

and suggested that unless there is monitoring of independent IRB's by

OPRR, they should not be allowed to approve research under this rule.

The agency received other comments asserting that independent IRB's are

well-qualified to maintain the requisite oversight and responsibilities

of emergency research trials and that independent IRB's can maintain

ethical standards equivalent to dependent IRB's.

As previously discussed in the preamble to the proposed rule, the

agency thinks that independent IRB's can properly review this type of

research. The agency thinks that duly constituted IRB's can ensure that

the rights and welfare of research subjects are protected by fulfilling

the requirements of part 56 (21 CFR part 56) and Sec. 50.24, including

Sec. 50.24(a)(7) requiring public disclosure as well as consultation

with the communities from which the subjects will be drawn. FDA

anticipates that this type of research will usually be performed in an

institution with an IRB. In that case, the IRB for the institution has

the responsibility and authority to review all studies performed in the

institution. This review responsibility may not be delegated to another

IRB unless the institution and the IRB for the institution agree to the

delegation and the agreement is documented in writing.

5. Conflicts with Statutes, the Constitution, and Other Standards

19. One comment stated that the rule conflicts with State common

law--that is, a physician who performs research without obtaining

consent for that research will be liable under common law for

malpractice and battery, and is likely to lose his or her license. This

comment stated that by adopting the proposed rule, FDA is overstepping

its authority by attempting to regulate the practice of medicine and by

attempting to override State law, and that FDA lacks the authority to

permit anyone in the medical profession to practice without obtaining

consent.

FDA disagrees with the comment. This rule does not attempt to

regulate the practice of medicine. Rather, as discussed more fully in

the preamble to the proposed rule, FDA is regulating investigational

products under the statutory authority contained in the Federal Food,

Drug, and Cosmetic Act (the act). FDA also disagrees with the comment

that FDA is overriding State law. As stated elsewhere in this preamble,

FDA is not changing the existing Federal policy that recognizes the

continuing validity of applicable State or local laws and regulations

on human subject protections. With regard to physician liability for

performing research under this regulation, FDA disagrees with the

comment's blanket conclusion that physicians participating in such

research are committing malpractice and battery. FDA notes that this

rule does not override existing State and local laws and regulations

that may apply to such research. Institutions wishing to participate in

such research may wish to consult their attorneys regarding any State

and local restrictions that preclude such research. As with other

research, physician liability for activities engaged in during

emergency research will vary from State to State because of different

laws on human subject protections. FDA notes that an existing

regulation Sec. 50.23 permits waiver of informed consent in certain

limited emergency situations. FDA is unaware of any research conducted

in accordance with that regulation that has resulted in physician

liability for malpractice or battery.

20. One comment stated that the proposal violates Federal law under

the Patient Self-Determination Act of 1990.

FDA disagrees with the comment. The Patient Self-Determination Act

of 1990 defines an advance directive as ``a written instruction, such

as a living will or durable power of attorney for health care,

recognized under State law (whether statutory or as recognized by the

courts of the State) and relating to the provision of such care when

the individual is incapacitated.'' (42 U.S.C. 1395cc(f)(3).) That act

imposes obligations on certain facilities (hospitals, skilled nursing

homes, home health agencies, and hospice programs) participating in the

Medicare program regarding advance directives. (42 U.S.C. 1395cc.) The

Patient Self-Determination Act requires these facilities to give

information to patients about their rights under State law to accept or

refuse treatment and to make advance directives. These facilities also

are required to document in the patient's medical records whether the

patient has executed an advance directive and to ensure compliance with

State laws on advance directives. The comment did not explain how he

believed the rule violates the Patient Self-Determination Act; nothing

in this rule prevents facilities from continuing to act in compliance

with the requirements contained in that act.

21. Another comment questioned the validity of the claim in the

proposal that ``the proposed rule gives double weight to the statutory

'necessitates' criterion'' because ``(1) intervention is needed because

of the medical condition, and (2) the collection of valid data is

needed

[[Page 51505]]

because of the absence of proven satisfactory available treatment for

the condition.'' This comment stated that the context of the

``necessitates'' clause makes it clear that what is necessary is the

use of a device to preserve the life of the subject--that the

relationship of necessity is between the intervention and the subject's

condition. This comment stated that it is a perversion of the statutory

language to claim that it uses ``necessitates'' to refer to the

relationship between the collection of data and proven treatment. The

comment noted further that randomly assigning subjects to a treatment

that some researchers consider unsatisfactory and to a treatment

researchers think may be an improvement is not necessitated by the

subject's life-threatening condition and, further, a placebo can never

be necessitated to preserve a subject's life.

The agency agrees that the ``necessitates'' clause focuses on the

relationship between the treatment and the subject's condition. The

idea that an intervention using an investigational product is

``necessary'' may, at first, appear to be contradictory. It does not

mean the product is safe and effective and that it must be given to

everyone. Read this way the exception would apply to products that are

not investigational and it would be irrelevant. The device amendments

to the act are referring to an investigational intervention that is not

known to be beneficial, and ``necessitate'' means that because

available therapy is inadequate, potentially beneficial intervention is

needed. Thus, there is no obligation to give everyone the

investigational intervention despite the patient's need for some better

treatment; it is possible to give only some subjects the intervention,

leaving others to the care they would get were there no study. In the

absence of an obligation to give every patient the investigational

intervention, it is possible to consider other factors, such as the

need to evaluate the intervention and learn from the exposure, which

potentially may benefit the subject in the study, the community, and

future patients with the disease. The critical and potentially

difficult concept is that the intervention is given because the

patient/subject needs it, yet enough is not known about the

intervention to support giving it to everyone as therapy.

It is clear, despite the uncertainty, that the investigational

intervention is intended to be beneficial and that there is conceptual,

preclinical, and possibly clinical (e.g., other settings, preliminary

results) evidence that the hoped for benefits outweigh the potential

risks, all of which leads the investigator (and the pertinent IRB) to

hope for, even anticipate, benefit. Such anticipation is compatible

with the state of clinical equipoise needed to allow a clinical

investigation. Indeed, true neutrality is rarely present at the start

of an investigation; in the absence of expectation that an intervention

may represent an improvement, or a belief that a standard therapy might

not work, there is little incentive to proceed. The experienced

clinical investigator, however, also knows that expectations are not

the same as knowledge and that disappointments are too common to

ignore. Therefore, despite optimistic expectations, one can be in the

state of equipoise needed to allow a clinical investigation to be

conducted.

In the current rule, addressing the special case of nonconsenting

subjects, the agency is asking for more than the usual assurances that

the investigational intervention is promising, and that accumulating

results have not taken us all the way past equipoise (through the data

monitoring committee's considerations). This extra assurance is

necessary because it must be possible to state honestly that the

intervention is for the patient's benefit, at least at the level of

being promising, and is not a project only for pure science, future

generations, or the community, although it will, of course, benefit

those too.

Therefore, if there are available only unproven or unsatisfactory

therapies and appropriate animal and other preclinical studies support

the potential of benefit to subjects from a new intervention, the

agency thinks it can be said that the subject's condition

``necessitates'' alternative treatment. In the case under

consideration, where the new intervention is not known to be of value,

although it is promising and has been evaluated in animals and in less

emergent settings, it is reasonable to randomize to a standard therapy

not yet shown inferior to the new intervention. The subject receiving

standard therapy is no worse off than if there had been no clinical

investigation.

22. Another comment considered the rule contrary to the Nuremberg

Code and to the U.S. Constitution; it stated that the agency's reliance

on Doe v. Sullivan is inappropriate. Another comment suggested that the

decisions of the U.S. Supreme Court in Cruzan v. Director Mo.

Department of Health, and Griswald v. State of Connecticut present

constitutional barriers to the proposal to eliminate the requirement of

informed consent in biomedical research involving emergency conditions.

This comment also analyzed an attorney's observations at the Public

Forum with respect to State law and criticized the proposal for not

addressing these. Another comment stated that the rule denies persons

with disabilities equal protection under the law and their rights to

due process in that it treats competent and incompetent patient-

subjects in a distinct, unequal manner.

FDA disagrees with these comments and with the assertions that the

cases cited present constitutional barriers to the issuance of this

rule. FDA strongly endorses the concept of informed consent. Obtaining

informed consent is not always possible, however, as Congress has

recognized in enacting amendments to the Act. Congress explicitly has

authorized exceptions from the requirement for informed consent in

research in limited situations. (See preamble to the proposed rule for

a more detailed discussion of authority in the act for permitted

exceptions from informed consent (60 FR 49086)).

Unlike situations involving a failure to inform a competent person

of the risks and consequences associated with participating in research

(see In Re Cincinnati Radiation Litigation, 874 F. Supp. 796, 800-01

(S.D.Ohio 1995)), this rule seeks to maximize an individual's access to

potentially beneficial drugs and devices at a time when, due to an

emergency which causes incompetency, informed consent cannot be

obtained. The issuance of this rule does not result in the automatic

entry of an individual in a clinical investigation without informed

consent. Rather, it contains important protections that must be met

before such a clinical investigation may proceed. Decisions on whether

an investigation may proceed will be made on a case-by-case basis by

individual IRB's and need the concurrence of a licensed physician.

Contrary to the comment's suggestion, the Supreme Court's decision

in Cruzan v. Director Mo. Department of Health does not create a hurdle

to the issuance of this rule. In Cruzan v. Director Mo. Department of

Health, 497 US 261 (1990), the Supreme Court, in reviewing a Missouri

statute which required clear and convincing evidence of an incompetent

person's wishes as to whether or not life-sustaining treatment should

be employed, balanced a State's interest in the preservation of life

with an individual's wish to terminate life support rather than remain

in a vegetative state. Unlike Cruzan, this rule focuses on the

preservation of life when an individual's wishes are unknown. As in

other emergency situations, where an individual is incompetent, if it

is feasible to obtain informed consent from the individual's legally

authorized

[[Page 51506]]

representative, then such consent should be obtained. FDA notes that it

is possible that an individual may have previously issued advance

directives on life-sustaining treatment. FDA believes that, where

feasible, attempts should be made consistent with State law to identify

the existence of such directives prior to enrolling an individual into

a clinical investigation without informed consent. FDA recognizes,

however, that in many life-threatening instances it may not be feasible

to learn of the existence of any existing directives prior to taking

potentially life-saving intervention and that in many instances, an

individual may not have issued such advance directives. In such cases,

FDA believes that interventions consistent with this rule are

constitutionally permissible.

H. Clarifications

23. HIMA noted that it was one of the organizations that endorsed

the October 25, 1994, consensus document on Informed Consent in

Emergency Research from the Coalition Conference of Acute Resuscitation

and Critical Care Researchers.

The agency acknowledges that HIMA endorsed the consensus document

on Informed Consent in Emergency Research from the Coalition Conference

of Acute Resuscitation and Critical Care Researchers.

24. HIMA also suggested that FDA recognize the diversity of opinion

on ``deferred consent'' and its history of successful use from

approximately 1980 until mid-1993, rather than simply disregard this

concept as ``post-hoc ratification'' unworthy of ``genuine'' informed

consent.

FDA disagrees and thinks that its earlier rejection of ``deferred''

consent was appropriate. As described in the preamble to the proposed

rule, posthoc ratification is not genuine consent because the subject

or representative has no opportunity to prevent the administration of

the test article, and cannot, therefore, meaningfully be said to have

consented to its use.

III. Specific Comments on the Proposed Regulation

A discussion of the specific comments received in response to this

proposal follows:

A. Definitions

25. Four comments requested clarification of the proposed

definition of family members in Sec. 50.3. Two comments questioned what

one should do if there is disagreement among family members. One asked

whether a family member could provide informed consent for emergency

research if State law does not explicitly provide for consent from

family members. Another questioned whether family members, even those

who do not possess power of attorney for health care rights, can

provide informed consent for emergency research under this rule.

One individual suggested that it may be unwise to provide a new

definition for such a familiar expression as ``family member'' and

suggested that the phrase ``any individual related by blood or affinity

whose close association with the subject is the equivalent of a family

relationship'' be used in its place. Another comment commended the

agency for including in its definition those individuals whose

relationship resemble family relationships.

One comment suggested that the hierarchy of the decision-making

authority of family members should be clearly stated. This comment

questioned whether one family member could overrule the decision of

another and questioned whether all family members must agree.

The agency thinks that it is appropriate to retain the phrase

``family member'' and its definition. The agency has specifically

included family members under this rule because the opportunity for an

available family member to object to a potential subject's

participation in such a clinical investigation provides an additional

and an important protection to these individuals. Otherwise, if consent

from a subject or the subject's legally authorized representative were

not feasible, the eligible individual could be enrolled into the

investigation. Thus, by permitting a family member (even one who is not

a legally authorized representative) to object to an individual's

inclusion in the investigation, a further protection is provided to

that individual. This rule has been modified to make clear that a

family member must be provided an opportunity to object to the

potential subject's participation, if feasible within the therapeutic

window when obtaining informed consent from the subject is not feasible

and a legally authorized representative is not available. The agency

recognizes that this may not constitute legally effective informed

consent if the family member is not a legally authorized representative

under State law. FDA is not establishing a hierarchy of family members

although an IRB may consider the need for creating a hierarchy in

reviewing individual investigations. Under this rule only one family

member would need to be consulted and agree or object to the patient's

participation in the research. If family members were to disagree, the

researcher and family members would need to work out the disagreement.

26. One individual, who was opposed to the entire rule, suggested

that by not providing a definition of ``emergency,'' FDA's quest for

harmony and uniformity would be defeated by the various definitions

provided by State law. He suggested that without such a definition, too

much discretion is delegated to medical researchers and IRB's; that the

agency will have little basis to monitor the activities carried out by

these researchers; and that the exception will be used to exempt all

emergency research from consent, even when it is feasible to

prospectively identify and secure the consent of hospitalized

individuals. Finally, he noted that the Health Care Financing

Administration has issued regulations under the Emergency Medical

Treatment and Active Labor Act which define the term ``emergency

medical condition;'' this act's regulations link an emergency medical

condition to the manifestation of ``acute symptoms of sufficient

severity * * * such that the absence of immediate medical attention

could reasonably be expected to result in: (a) Placing the health of

the individual * * * in serious jeopardy; (b) serious impairment to

bodily functions; [or] (c) serious dysfunction of any bodily organ or

part.'' He suggested that health care professionals will be confused by

the different use of the term ``emergency'' in this regulation and

under the Emergency Medical Treatment and Active Labor Act.

The agency disagrees with these comments. Sufficient guidance is

given in the regulation in Sec. 50.24, particularly in

Sec. 50.24(a)(2)(iii), to ensure that there is a clear understanding of

what constitutes a life-threatening situation that could invoke this

rule and to ensure that it is not used routinely in all emergency

research. In addition, each clinical investigation will be reviewed by

FDA and the IRB to help ensure that this exception from informed

consent is not used for research for which it was not intended.

Further, emergency room personnel should not be confused because they

should know when they are participating in FDA regulated research. The

agency notes that the purpose of the Emergency Medical Treatment and

Active Labor Act is different from this rule. This informed consent

exception is intended to allow certain FDA-regulated research to

proceed without informed consent provided specific conditions are met.

Entities that deal with both regulations

[[Page 51507]]

will be able to understand whether one or the other regulation applies.

B. Exception Criteria

1. Section 50.24(a)

27. One comment suggested that additional conditions be added to

Sec. 50.24(a) to reinforce the statement in the preamble to the

proposed rule that appropriate evidence is available to document

clinical equipoise and to ensure that efforts are made to obtain

consent from a legally authorized representative whenever possible. The

two proposed additional sections would read: ``[a]ppropriate animal and

preclinical trial studies have been completed, and the information

derived from those and related studies support the likelihood of

providing a direct benefit to the individual subjects'' and ``[t]he IRB

finds that the researcher defined the length of the therapeutic window

based on scientific evidence, will try to contact the legally

authorized representative within that window of time, and will ask each

representative contacted for consent within that window rather than

waive consent. The researcher will track the number of representatives

contacted and provide that information to the IRB.''

The agency agrees that these are important concepts that should be

contained explicitly in the regulation. It has incorporated these

comments in the regulation, with slight modification to the language

proposed in the comment. The agency has added a new paragraph to

Sec. 50.24(a)(3) to read as follows: ``(ii) Appropriate animal and

other preclinical studies have been conducted, and the information

derived from those studies and related evidence support the potential

for the intervention to provide a direct benefit to the individual

subjects.'' The agency also has added a new paragraph Sec. 50.24(a)(5)

and a new paragraph Sec. 50.24(a)(7)(v). The new paragraph

Sec. 50.24(a)(5) reads as follows: ``(5) The proposed investigational

plan defines the length of the potential therapeutic window based on

scientific evidence, and the investigator has committed to attempting

to contact a legally authorized representative for each subject within

that window of time and, if feasible, to asking the legally authorized

representative contacted for consent within that window rather than

proceeding without informed consent. The investigator will summarize

efforts made to contact legally authorized representatives and make

this information available to the IRB at the time of continuing

review.'' The new paragraph Sec. 50.24(a)(7)(v) reads as follows: ``(v)

If obtaining informed consent is not feasible and a legally authorized

representative is not reasonably available, the investigator has

committed, if feasible, to attempting to contact within the therapeutic

window the subject's family member who is not a legally authorized

representative, and asking whether he or she objects to the subject's

participation in the clinical investigation. The investigator will

summarize efforts made to contact family members and make this

information available to the IRB at the time of continuing review.''

The agency notes that if the window of time is narrow, it will be

difficult or impossible to identify a legally authorized representative

or family member, especially for potential subjects whose identities

are unknown at the time of presentation.

28. One comment suggested that, in order to prevent abuses, the

agency provide all IRB's with standardized forms that strictly define

the circumstances and process for an IRB to invoke the waiver of

informed consent.

The agency does not think that standardized forms would be useful

or practical. The regulation provides sufficient information and allows

flexibility for each IRB to develop procedures and methods (and forms,

if necessary) to fulfill its requirements.

29. Several wording changes were suggested to clarify

Sec. 50.24(a). Two comments suggested that Sec. 50.24(a) be revised to

add ``prior to initiation of research'' after the words ``without

requiring that informed consent be obtained'' in order to stress that

consent is being waived for the necessary immediate intervention.

The agency thinks this change is unnecessary. This is clear from

Sec. 50.24(a)(2) and new Sec. 50.24(a)(5).

30. One comment suggested the addition ``of all research subjects''

following the phrase ``without requiring that informed consent'' and

modifying the parenthetical phrase in the next sentence to read:

``(with the concurrence of a licensed physician voting member of the

IRB or the concurrence of a licensed physician who serves as a

consultant).''

The agency has incorporated this language, with minor changes, to

emphasize the need for concurrence by a licensed physician who is

either an IRB member or consultant and who is not otherwise

participating in the clinical investigation. The agency recognizes that

in some instances it will be possible to obtain informed consent from

some individuals or their legal representatives, or contact a family

member when this exception is invoked for a clinical investigation. The

agency has not included the term ``voting'' because it does not believe

that it is necessary to explicitly require that this licensed physician

who concurs be a voting member of the IRB because concurrence by this

licensed physician is required by the regulation. Since 1981, FDA has

stated its expectations that an IRB that reviews investigational new

drug studies will include at least one physician. (See 46 FR 8942 at

8966, January 27, 1981.) This expectation is not changed by this rule.

31. Other comments were received on the ``concurring licensed

physician member or consultant.'' Three comments felt that this

physician member or consultant would add nothing to the process because

of pressure to endorse the study; one comment suggested that the

interests of subjects would be better served if this physician or

consultant were independent of the IRB; two comments suggested that the

physician be independent of the investigator (i.e., have no ties to or

be in the same department or supervised by, the investigator).

The requirement for a concurring licensed physician is contained in

the Medical Device Amendments of 1976 and, thus, it must be retained.

The agency agrees with the need for this individual to be independent

from the clinical investigation but disagrees with the suggestion that

the physician be independent of the IRB. Thus, the agency has amended

the language in Sec. 50.24(a) to make clear that the licensed physician

must be one who is not otherwise participating in the clinical

investigation. This language parallels the language contained in

Sec. 50.23(a).

32. One of these comments suggested that an independent ombudsman

who is aware of the acute risks of the specific research, the long term

risks of the research for the individual, family, and society, based on

the condition of the potential subject be appointed to oversee the

study.

The agency does not agree. There is no need for a special

requirement for an ombudsman for these clinical investigations. Current

Sec. 50.25(a)(7) requires the consent form to contain an ``explanation

of whom to contact for answers to pertinent questions about the

research and research subjects' rights, and whom to contact in the

event of a research-related injury to the subject.'' It may be the IRB

or some other designated individual who performs these ombudsman-type

functions for these investigations.

[[Page 51508]]

2. Section 50.24(a)(1)

33. A few comments expressed concern about the phrase contained in

Sec. 50.24(a)(1) that ``available treatments are unproven or

unsatisfactory.'' One comment suggested that ``unproven'' be changed to

``ineffective.''

The agency disagrees with this suggestion because one may have

insufficient data to know whether a treatment is ineffective. One may,

however, know from the limited data available that it is ``unproven.''

34. Another comment suggested that the phrase ``available

treatments are unproven or unsatisfactory'' be changed to read ``the

efficacy of available treatments has not been demonstrated, or is

regarded as unsatisfactory.''

The agency does not believe this change is necessary or desirable.

Available treatments need to be assessed in terms of both safety and

effectiveness. The agency believes that the change proposed in the

comment focuses solely on effectiveness.

35. Another comment expressed concern that nonscientific members of

IRB's will have a particularly difficult time making determinations

about whether available treatments are unproven or unsatisfactory.

The agency disagrees. Current Sec. 56.107(a) requires the IRB

membership to possess the professional competence necessary to review

specific research activities. Further, current Sec. 56.107(f) permits

an IRB to invite ``* * * individuals with competence in special areas

to assist in the review of complex issues which require expertise

beyond or in addition to that available on the IRB.'' Thus, the IRB

should have sufficient information from its own professional expertise,

or from consultants, to make determinations about whether available

treatments are unproven or unsatisfactory.

36. One comment suggested that guidance on the criteria for

determining that current therapy is unsatisfactory should be provided

or that the rule should explicitly recognize that IRB's have the

discretion to make independent decisions on this point. One comment

suggested that a study be allowed to proceed if there is an alternative

therapy, provided that equipoise exists between the investigational

product and current therapy.

It is clear from the existing wording in Sec. 50.24(a) that it is

the IRB's responsibility to make decisions as to whether the criteria

in the rule are met. The agency notes that it will also be reviewing

these clinical investigations and will evaluate whether these

investigations meet the criteria in this regulation. There is nothing

in this rule that would prohibit an investigation from proceeding if

there is an alternative therapy where the alternative therapy is

unproven or unsatisfactory. The agency expects that in most clinical

investigations under this rule, the experimental intervention will be

added to standard therapy. That is, subjects in the investigation would

receive standard therapy, with a portion of the subjects receiving the

investigational product in addition. In some clinical investigations,

some subjects may receive standard therapy, while others may receive

the investigational product instead of standard therapy because, for

example, use of the investigational product precludes use of the

standard treatment. In these latter investigations, the IRB may need to

look more closely at why standard therapy is unproven or

unsatisfactory, and may want to review additional preclinical data or

results in less ill human subjects that the intervention is promising,

because the standard care will not be provided to a portion of the

subject population.

37. Other comments suggested that without clear definitions for

``unsatisfactory'' and other terms used in the proposal's preamble to

describe clinical equipoise, i.e., `unknown,'' ``believe,'' and

``reasonable minority,'' that abuse of the consent exception is likely.

The agency disagrees with these comments. The agency has explained

this provision in more detail in the preamble to the proposed rule and

believes that such definitions are unnecessary. The agency also notes

that the conduct of this research will be carefully monitored and will

be subjected to public scrutiny through the requirements for community

consultation and community disclosure. In the preamble to the proposed

rule, the agency stated that ``[w]hen the relative benefits and risks

of the proposed intervention, as compared to standard therapy, are

unknown, or thought to be equivalent or better, there is clinical

equipoise between the historic intervention and the proposed test

intervention. Clinical equipoise would exist * * * whenever at least a

reasonable minority of medical professionals believe the experimental

treatment would be as good as, or better than, the standard

treatment.'' (60 FR 49086 at 49093, September 21, 1995.) The agency

thinks that this description provides sufficient guidance to IRB's and

that it is appropriate to allow IRB's to determine when clinical

equipoise exists.

38. A number of comments suggested that the scope of the research

covered by the proposed rule and contained in Sec. 50.24(a)(1) be

extended to conditions beyond those that are immediately life-

threatening so that conditions that result in permanent disabilities,

such as a long-term or permanent coma, or conditions that would result

in other serious irreversible injury are included under the rule. One

example given was a near-drowning patient resuscitated in the

prehospital setting who arrives at the Emergency Department comatose;

the acute injury may no longer be immediately life-threatening, but the

chances that the patient will regain consciousness again are highly

unlikely. One comment noted that FDA has in the past interpreted

``life-threatening'' to include threats of serious disability and, if

this is intended in the proposed rule, it would be helpful to add this

interpretation to the supplementary information. Another comment

suggested that both stroke and head injury do not necessarily

immediately result in death and that potentially effective treatments

are being developed for these conditions which may leave the patient

with profound deficits. This comment proposed that such emergencies be

covered under the final rule. Two comments suggested that ``life-

threatening'' be defined and limited to include only those situations

believed to be immediately life-threatening. Another comment suggested

that ``emergency privilege'' is limited and should extend to care

needed to stabilize or prevent further deterioration of the patient's

condition as well as care necessary to prevent death or serious bodily

injury or harm. Therefore, the care justified must be balanced with the

emergent nature of the patient's condition, the patient's potentially

transient incompetence to make decisions and give consent, and the time

needed to make a reasonable effort to contact and involve the patient's

family.

The agency notes that the Medical Device Amendments limit this

exception to life-threatening situations; the agency and the IRB will

need to judge each clinical investigation to ensure that it meets the

criteria of the statute and regulations. Specifically, the IRB must

conclude that the intervention to treat a life-threatening condition

must be administered before consent can be obtained.

The criteria contained in the rule do not require the condition to

be immediately life-threatening or to immediately result in death.

Rather, the subjects must be in a life-threatening situation requiring

intervention before

[[Page 51509]]

consent from a legally authorized representative is feasible. Life-

threatening includes diseases or conditions where the likelihood of

death is high unless the course of the disease or condition is

interrupted. (See Sec. 312.81.) People with the conditions cited in the

examples provided in the comments--e.g., long-term or permanent coma,

stroke and head injury--may survive for long periods but the likelihood

of survival is not known during the therapeutic window of treatment.

People with these conditions are clearly at increased risk of death due

to infection, pulmonary embolism, progression of disease, etc. The rule

would apply in such situations if the intervention must be given before

consent is feasible in order to be successful. The informed consent

waiver provision is not intended to apply to persons who are not in an

emergent situation, e.g., individuals who have been in a coma for a

long period of time and for whom the research intervention should await

the availability of a legally authorized representative of the subject.

39. The agency received a number of comments on the reference to

placebo-controlled trials in Sec. 50.24(a)(1). One comment stated that

it was vitally important to retain the reference. Other comments

requested that the reference be removed. Reasons given for its removal

included concern that placebo-controlled studies will not meet the

requirement of clinical equipoise unless the placebo control is the

standard of care for the situation or there is absolutely no standard

therapy; that this conflicts with agency statements that the use of a

placebo is not necessary when the end-point is clear and reasonably

predictable; it is inappropriate for the agency to specify one study-

design among many; and that unless the potential subject or legally

authorized representative can consent, a placebo should not be an

alternative.

Some of the comments appear to presume that in a placebo-controlled

trial, the placebo group would be untreated. In virtually all cases,

when a placebo is used, standard care, if any, would be given to all

subjects, with subjects randomized to receive, in addition, the test

treatment or a placebo. An exception to this would be the situation in

which the test is to determine whether standard treatment is in fact

useful. In that case, there must be a group that does not receive it.

The agency believes that it is important to recognize in the regulation

that placebo-controlled trials may be conducted under this emergency

research provision; thus, it is retaining the wording in this section.

Different kinds of controls are described in FDA's regulations. For

example, FDA regulations for drugs (Sec. 314.126) describe five kinds

of study designs that can be used in carrying out the well-controlled

investigations needed under law to provide the ``substantial evidence

of effectiveness'' needed to market a drug. They are: Placebo

concurrent control, dose-response concurrent control, no-treatment

concurrent control, active treatment concurrent control, and historical

control. In any given year, drug approvals will be based on clinical

investigations using each of these designs. The study design used must,

however, be adequate to the task of providing evidence that the drug or

device will have the effect claimed.

40. Two comments suggested changing the wording of Sec. 50.24(a)(1)

from ``what particular intervention is most beneficial'' to ``the

safety and efficacy of a particular intervention'' in order to provide

greater flexibility. Another comment suggested that ``most beneficial''

be followed by the clarifying phrase ``to patients in the life-

threatening situation.''

The agency agrees that it would be more precise to indicate that

the clinical investigation is necessary to determine whether a

particular intervention is safe and effective and it has modified the

wording in the regulation accordingly.

3. Section 50.24(a)(2)

41. A number of comments on Sec. 50.24(a)(2)(ii) recommended that

``or family members'' be added to ``legally authorized

representatives'' at each occurrence in the proposal and in its

conforming amendments in order to ensure that the exception is used

only in those cases where it is not feasible to contact the legally

authorized representative or a family member.

The agency generally agrees with these comments for the reasons

previously stated and has modified the regulations accordingly.

42. Two comments requested that a definition of the term ``legally

authorized representative'' be provided. One comment suggested that the

language be clarified to read ``* * * consent from the subjects'

legally authorized representatives is feasible.''

``Legally authorized representative'' is currently defined in

Sec. 50.3(m) to mean ``an individual or judicial or other body

authorized under applicable law to consent on behalf of a prospective

subject to the subject's participation in the procedure(s) involved in

the research.'' This definition is being retained in the regulation.

The agency has added the clarifying language that it is ``the

subject's'' legally authorized representative.

43. One comment questioned whether one should seek oral consent/

assent from a family member or other individual in those instances in

which there may only be a few moments to convey the nature of the

intervention, precluding full informed consent. If such assent is not

given, the comment requested clarification on options available to the

researcher.

If it is feasible to obtain informed consent for some potential

subjects, informed consent is required for those individuals. If there

is insufficient time to obtain informed consent for some potential

subjects, but there is sufficient time to convey some basic risk and

benefit information about the clinical investigation, then that

information should be provided to the subject, the subject's legally

authorized representative, or the subject's family member. If the

subject, legally authorized representative, or family member objects to

the individual's inclusion in the investigation based upon the

information provided, then that individual should be excluded from

participation in the clinical investigation. If only partial

information was conveyed, then the information described in

Sec. 50.24(b) is to be provided at the earliest feasible opportunity.

44. Another comment suggested that there be a requirement that the

determination that a subject cannot provide informed consent and

efforts made to obtain informed consent from the subject's legally

authorized representative be documented and notarized by an individual

not directly involved in the research. This comment suggested that

without such a requirement, investigators are likely to make little

effort to obtain consent from subjects prior to enrollment. This

concern was echoed by another comment, which suggested that the

investigators' documentation of efforts to obtain informed consent

would encourage researchers to expend greater efforts to obtain

informed consent for these activities. Another comment suggested that

this documentation be made by an individual not affiliated with the

study team.

The agency expects the IRB to determine, based on the specific

details of the individual clinical investigation (including the window

of opportunity for treatment), the procedures the investigator must

follow to attempt to obtain informed consent before enrolling a subject

in an investigation without such consent. The agency has added a new

paragraph Sec. 50.24(a)(5) that requires the investigator to attempt to

[[Page 51510]]

contact a legally authorized representative for each subject within the

therapeutic window and, if feasible, ask for consent within that window

rather than proceeding without consent. The agency also has added a new

paragraph Sec. 50.24(a)(7)(v) that requires the investigator to attempt

to contact a family member within the therapeutic window and ask

whether the family member objects to the subject's participation in the

clinical investigation, if informed consent is not feasible and a

legally authorized representative is not available. IRB's may create a

hierarchy of family members or impose other conditions to increase the

protections provided to research subjects. These paragraphs further

require the investigator to summarize efforts made to contact

representatives and family members and to make this information

available to the IRB at the time of continuing review. The agency

believes that these procedures will ensure that appropriate efforts are

made by the investigator to obtain consent from subjects prior to

enrollment. The agency expects these procedures to be documented in the

protocol and/or by the IRB, and the efforts made by investigators to be

documented in the material presented to the IRB for its continuing

review. The agency believes that this documentation provides the

necessary protections suggested by these comments.

45. One comment suggested that Sec. 50.24(a)(2)(iii) be modified to

read ``There is no reasonable way to identify prospectively the

individuals likely to become eligible for participation in the research

study,'' omitting the remainder of the sentence.

The agency agrees that the last phrase in the proposal that read

``because the emergence of the condition to be studied cannot be

predicted reliably in particular individuals'' is not needed and it has

therefore deleted this phrase from the final rule as suggested.

46. Although two comments stressed the importance of retaining the

word ``reasonable'' in order to allow IRB's to exercise the judgment

necessary to make satisfactory decisions about application of the

exception in particular contexts, another comment suggested that the

term ``reasonable'' may provide more flexibility than is desirable.

The agency thinks that IRB's must be allowed to make responsible

judgments when they review clinical investigations, and that it is

important to retain the term ``reasonable'' in order to permit the IRB

to judge the particular circumstances surrounding each investigation

under review.

47. One comment asked how to document the case where prospective

individuals have been notified and prior consent for participation has

been sought in an institution with several co-investigators or where

more than one institution in the area may be participating in the

research. The comment asked further whether only those subjects with

the condition who gave prior consent could be enrolled and whether

those who did not render a decision would be excluded from

participation in the study.

Generally, the agency recommends that when prospective consent is

being sought in an institution, the documentation that a potential

subject consented or refused to consent be placed prominently in the

subject's medical file. Consent will typically be documented through a

signature on the consent form. It is the responsibility of the clinical

investigator to determine how to identify prospective subjects who have

agreed or refused to participate in a clinical investigation if they

should become eligible in order to help ensure that their decisions are

followed. When an IRB determines that it is not appropriate to waive

the requirement of informed consent because there is a reasonable way

to identify prospectively the individuals likely to become eligible for

the clinical investigation, then only those subjects with the condition

who gave prior consent may be enrolled in the investigation. Those

individuals who either did not make a decision or who refused would be

excluded from participation in the investigation.

48. Another comment noted that if a subset of the general

population can be identified as potential subjects, anticipatory

informed consent must be obtained, even if the subset is a very small

percentage of a large patient population. For example, where a small

percentage of patients undergoing a standard procedure may suffer a

complication that would render them unconscious and make them potential

subjects, informed consent should be obtained for that clinical

investigation. The comment went on to note that if that procedure

carries some known risk for a complication, the potential subjects

would need to be informed of that risk in any event, and obtaining

anticipatory consent for the investigation should therefore not be

burdensome.

The agency generally agrees with the concept that obtaining

anticipatory consent from a target population where the complication

rate is modest often would be feasible. As the complication rate grows

small and the population hard to identify, this strategy becomes

problematic. Each clinical investigation must be judged individually by

FDA and the IRB.

49. Another comment suggested that the Coalition Conference

Consensus Statement wrongly discounted the value of securing and the

ability to secure prospective consent from identifiable individuals at

high risk for study enrollment, particularly those in hospitals, and

that neither the consensus statement nor the proposed rule mentioned

the role of advance medical directives in guiding enrollment decisions.

This comment, supported by others, suggested that a good faith effort

should be mandated to locate advance directives and that the regulation

should include a new paragraph, as follows: ``Any individual likely to

be eligible for a research protocol under this section may not be

enrolled in the research if the investigators know, or reasonably

should know, that the individual did not want to receive medical

interventions of the type under study.'' Another comment suggested

that, although advance directives have been addressed in clinical

practice, their application to the conduct of clinical research has not

received much scrutiny. This comment described the difficult task for

potential subjects to imagine the kind of research they would want

should they suffer a catastrophic illness; it went on to recommend that

either FDA clarify how it intends clinical investigators to adopt the

practice of advance consent, or this statement should be deleted. It

further suggested that FDA consider requiring the use of consent

auditors whose role would be to determine whether the subject truly

understands the consent process.

The agency does not believe that these comments require a change in

this regulation. The agency recognizes that it may be possible in some

situations to secure prospective consent from identifiable individuals

at high risk for study enrollment, particularly if they are inpatients.

It is for that reason that the agency has included

Sec. 50.24(a)(2)(iii), which requires the IRB to determine that there

is no reasonable way to identify prospectively the individuals likely

to become eligible for the clinical investigation. Both the American

Hospital Association's Patient Bill of Rights and section 4206 of the

Omnibus Budget Reconciliation Act of 1990 recognize a patient's right

to participate in and direct health care decisions affecting the

patient. The agency agrees, particularly for clinical investigations

involving inpatients, that

[[Page 51511]]

appropriate efforts be made to review the patient's medical file to

determine whether there exists an advance medical directive or other

indication of the patient's desires (e.g., do not resuscitate order).

However, the agency also recognizes that, for at least some of the

research that will be eligible for this exemption, there will be

insufficient time to search for or locate such directives. The IRB

should be knowledgeable about an institution's procedures regarding the

use of advance medical directives and assess whether the proposed

clinical investigation is consistent with those procedures.

As discussed previously, if an IRB determines that it is not

appropriate to waive the requirement of informed consent because there

is a reasonable way to identify prospectively the individuals likely to

become eligible for the clinical investigation, then only those

subjects with the condition who gave prior consent may be enrolled in

the investigation. Those individuals who either did not make a decision

or who refused would be excluded from participation in the

investigation. For research where individuals can give informed consent

prospectively, the individual's consent or refusal should be documented

in such a way to ensure that the individual's determinations are

followed. As in other research that is reviewed by an IRB, it is up to

the IRB to determine whether there is a need for a consent auditor.

50. Another comment recommended that the question of whether prior

consent of subjects must be obtained should be resolved by considering

the following questions: (1) From which populations will subjects be

drawn; (2) what is the probability that any particular member of the

at-risk population will become a potential subject; (3) where is the

population from which subjects will be drawn; (4) how much effort is

needed to inform the population of the study; and (5) what is the most

effective communications media or mechanism to reach the population.

Based on these questions, this comment recommended that a new section

be added that would state: ``When individuals likely to become eligible

for the research are members of identifiable and accessible populations

of the community at large, reasonable effort to target communications

to those sub-populations should be made.''

This comment suggests what may be a reasonable thought process for

an IRB to follow. However, it combines two different concepts:

communication with the community and prior consent of individual

subjects. As the agency has previously stated, if one can obtain prior

consent of subjects, that should be done. Examples of situations where

it may be feasible to obtain prior informed consent include: use of a

surgical procedure with a known severe consequence; administration of a

drug product with a known serious adverse reaction; identification of a

population with a particular disease or condition who are at an

extremely high risk for a serious event. In each of these instances, it

may be feasible to identify in advance the specific patient population

susceptible to the condition being studied and obtain consent. The

agency believes that it would be inappropriate to add the suggested

section to the regulation because it confuses efforts to inform the

community with efforts to obtain prior consent of the individual.

51. Another comment recommended that the agency require preliminary

studies of new products in patients admitted to intensive or critical

care units who are able to consent or who have a legal representative

who can consent on their behalf. This comment suggested that this would

strengthen an inadequacy in the existing regulations that permits

studies (with subjects unable to provide informed consent) to begin,

without any knowledge regarding the clinical performance of the drug/

device.

Given the nature of the product and the medical condition, this

suggestion may not be feasible for many of these clinical

investigations. The agency, in its review of these investigations, will

review the adequacy of the information about the proposed intervention

to help ensure that there is sufficient knowledge, including clinical

performance in other settings when possible, of the drug or device to

justify its use in such investigations. In addition, the regulation has

been modified to specify that evidence from appropriate animal and

other preclinical studies support the potential for the intervention to

provide a direct benefit to the individual subjects.

4. Section 50.24(a)(3)

52. A number of comments suggested deleting the phrase ``is in the

interests of the subjects'' in Sec. 50.24(a)(3) in part because this

phrase requires that a judgment be made about subjects whose interests

may be largely, if not totally, unknown to the IRB and to the

investigators. Some comments argued that there would be no possible

benefit to the subject, but only to society at large if the

experimental intervention were shown to be effective; the goal of the

research is not to benefit subjects in the research, but rather to

benefit science in the pursuit of knowledge. Others suggested that

Sec. 50.24(a)(3) be modified to read: ``The opportunity to participate

in the research holds out the prospect of direct benefit to the

subjects because * * *.'' Other comments objected to the word

``opportunity'' as being disingenuous and paternalistic and suggested

that this section be modified to read: ``Participation in the research

* * *.''

The agency agrees that Sec. 50.24(a)(3) should be modified in

response to some of these comments. The first comment points out that

one cannot really know about all the interests of a person in these

situations. The modification would make clear that the clinical

investigation holds out the prospect of direct benefit to the subjects.

The agency does not agree with the second comment that there would be

no possible benefit to the subject, but only to society at large. To

justify the use of this exception the IRB must believe that

participation in the study holds out the prospect of direct benefit to

the subjects. It is also true, but not the basis for the exception,

that the interests of society will be served by the waiver because the

research will produce valuable knowledge, applicable to future

patients, that would otherwise never be obtained; an IRB should not

approve a clinical investigation that is poorly designed and, thus,

unable to answer the scientific question posed. In response to the

third suggestion, the agency is clarifying any mis-impression that it

would be the ``opportunity'' rather than the actual ``participation''

in the research that is beneficial. The agency intended that

participation in the research should hold out the prospect of direct

benefit to the subject and has revised the rule accordingly.

53. Another comment noted that if the null hypothesis is plausible,

that is, if the effect of the investigational intervention is no

different from that of the standard treatment, the subject has little

to gain by being in a randomized trial rather than being treated by

whichever arm of the study is standard. This comment recommended that

historical controls be used when investigators or potential subjects

are not ``indifferent'' to the treatment alternatives.

If the use of a historical control is appropriate for the clinical

situation being studied, that control may be used, but the difficulties

of this design are well-known and it cannot reliably assess small, but

potentially meaningful benefits and is frequently associated with false

positive results. The comment related to the null hypothesis is not

unique to emergency research. Rather, it reflects a fundamental ethical

dilemma

[[Page 51512]]

in all clinical trials. This dilemma, however, has not been considered

by most bioethicists as an impassable obstacle for the conduct of

controlled trials. This is because continuing an intervention, even one

thought to have promise, without determining that it does provide

benefit, is not a responsible alternative. The investigational

intervention in these clinical investigations must be promising, but

one does not know that it is in fact safe and effective. Further, in

these investigations, the standard treatment being compared to the

investigational product or to which the investigational product is

added will be of unproven benefit or unsatisfactory.

54. One comment suggested that an additional condition be added to

50.24(a)(3) which would require that the weight of scientific evidence

be sufficient to support the likelihood that the individual subjects

will receive a direct benefit. Another comment suggested that the rule

require a progression of research from less severe medical cases to

more severe and only permit the inclusion of patients unable to consent

if there is an ombudsman independent from the research activity.

As previously described, FDA has added a new Sec. 50.24(a)(3)(ii)

which requires that ``Appropriate animal and other preclinical studies

have been conducted, and the information derived from those studies and

related evidence support the potential for the intervention to provide

a direct benefit to the individual subjects.'' There is nothing in this

rule that would preclude research from being conducted in subjects with

less severe medical conditions (not in a life-threatening situation)

before being conducted in subjects with more severe medical conditions

provided that informed consent is obtained from the research subjects

with the less severe conditions. When this exception is invoked for a

particular clinical investigation, however, the FDA, sponsor, clinical

investigator, and IRB will be responsible for ensuring that the subject

population is appropriate; that is, that the subjects are in a life-

threatening situation.

55. One comment recommended that Sec. 50.24(a)(3)(i) be reworded to

clarify that ``subjects are facing a life-threatening situation that

necessitates intervention.''

The agency agrees with the comment and has modified this section

accordingly.

56. One comment suggested that proposed Sec. 50.24(a)(3)(ii) be

reworded to clarify that the rule is addressing the ``prospective

subjects' condition'' and that ``current therapy'' equates to

``standard therapy.'' This comment suggested that proposed

Sec. 50.24(a)(3)(ii) be rewritten to state ``risks associated with the

intervention are reasonable in the light of what is known of the

prospective subjects' medical condition, the risks and benefits of

standard therapy * * *.''

The agency has renumbered proposed Sec. 50.24(a)(3)(ii) to be

Sec. 50.24(a)(3)(iii) in the final rule. The agency agrees with the

comment and has modified this section accordingly. The risk and benefit

assessment that is required by Sec. 50.24(a)(3)(iii) will be conducted

for future subjects meeting the entry criteria for the clinical

investigation; therefore, it is appropriate to refer to these subjects

as the ``potential class of subjects.'' The agency intended that the

risks and benefits of ``standard'' therapy be considered; it recognizes

that ``current'' therapy may be too broad.

57. Several comments requested a definition of ``reasonable.'' One

comment noted that the rule requires a complex judgment about risks and

benefits and yet lacks specificity as to how this judgment is to be

made. This comment noted that in most research, an IRB can rely on the

risks and benefits being explained to the subject and the subject

judging whether they are reasonable. In the case of the research

covered by this regulation, that recourse is not available.

It is not possible to be specific about how to make the judgment

about risks and benefits because, as the comment notes, the judgment to

be made is complex, with different information and considerations

determined by the particular clinical investigation. The agency thinks

that sufficient clarity is contained in Sec. 50.24(a)(3)(iii) to allow

an IRB to understand that it must consider: (1) What is known about the

medical condition, (2) what is known about standard therapy, and (3)

what is known about the proposed intervention or activity. The risks of

the investigation must be considered reasonable in relationship to all

of this information. The agency does not think that this requirement

needs further explanation.

58. Two comments suggested that proposed Sec. 50.24(a)(3)(ii) be

modified to incorporate the Coalition of Acute Resuscitation and

Critical Care Researcher's concept of ``appropriate incremental risk''

stating that this would better protect the rights of subjects. One of

these comments suggested that the 1981 FDA regulatory requirement that

``there is available no alternative method of approved or generally

recognized therapy that provides an equal or greater likelihood of

saving the life of the subject'' is the standard that should be used in

this regulation.

The agency disagrees with both suggestions. The protections

provided by the rule are substantial and sufficient without these

changes. The standard for risks, described in the regulation, are that

they be ``reasonable'' in relationship to what is known of the medical

condition of the potential class of subjects, the risks and benefits of

standard therapy, if any; and what is known about the risks and

benefits of the proposed intervention. The term ``appropriate

incremental risk'' does not have a clearly different meaning, although

it may imply greater precision than usually exists. In order to invoke

this exception, the available treatments must be unproven or be

regarded as unsatisfactory.

5. Section 50.24(a)(4)

59. Several comments suggested deleting or clarifying

Sec. 50.24(a)(4) concerning the ``practicability'' of conducting the

research without the waiver. One comment requested clarification as to

whether ``practicability'' only referred to whether there is sufficient

time to obtain consent from a subject's legally authorized

representative; and recommended that if this is the sole basis for

determining practicability, it should be added to the regulation.

Another comment noted that ``practicability'' should not refer to

convenience, cost, or speed. One other individual commented that

although certain institutions may be unable to perform specific acute

injury research because of logistical considerations, it is likely that

most research projects could be designed such that performance under

existing rules for nonconsenting subjects would be possible in other

locations. This comment cited a multicenter trial where only one

institution requested a waiver.

One comment suggested that Sec. 50.24(a)(2)(ii) is sufficient for

determining whether a study can be done; this comment stated that the

primary reason that it would not be practical to carry out the research

without the waiver would be because it is not feasible to contact the

legally authorized representative or family member before the

intervention must be administered.

Another comment objected to Sec. 50.24(a)(4) and argued that the

rule should state that if there are any potential subjects otherwise

eligible for a trial for whom consent from a legally authorized

representative cannot be obtained, the provisions of Sec. 50.24(a) may

be utilized to include them, even if the trial could be carried out

without

[[Page 51513]]

their participation, so long as all of the requirements for that

section are met. This comment noted that if this section meant only

that consent should be obtained wherever it can be, even when most

subjects in a study do not have an available legally authorized

representative, it would be unexceptionable, but the section goes

beyond that to proscribe participation in a trial by patients without

consent when the majority of eligible patients do have such consent

available because in that case the study can be carried out

``practicably'' without those patients. This comment noted that it is

the value of participation to the subject that permits an exception to

the informed consent requirement; that implicit in the proposal is the

view that most patients would choose a chance to receive promising

rather than standard therapy that is known to have an often

unsatisfactory outcome. Thus, to exclude patients unable to consent

from this research is unethical, even if the study could be conducted

with subjects for whom surrogate consent is possible.

The agency has carefully considered these comments, particularly

the latter comment that in effect contended that the ``practicably''

requirement is inconsistent with the ethical basis for the rule because

it implies that the exception to consent is available to serve the

community's needs rather than the individual's. The agency included

this requirement not because it thought the research was not in

individual patients' interests, but because research without informed

consent represents a more difficult and complex situation than research

with consent, in that it is a kind of research with greater than usual

ethical issues that should be taken only when necessary. This is

because the agency believes it is generally preferable to obtain case-

by-case consent even from a representative of the individual. Just as

consent by the subject is preferable to consent by their

representative, consent by the subject's representative is preferable

to the procedure in this regulation. This does not mean that these

procedures are inadequate or unethical; rather, it recognizes within

the realm of ethically proper actions a hierarchy of values and that we

should seek the highest level of those values feasible in this

situation.

Similar considerations have arisen in the past. The National

Commission for the Protection of Research Subjects of Biomedical and

Behavioral Research argued that (wherever possible) clinical trials

intended to benefit young children should first involve adult subjects,

later older children as subjects, and finally trials in younger

children (who cannot consent or assent). This is not because the trials

in younger subjects are considered inappropriate or ethically doubtful.

The agency understands the Commission to be saying that the principle

of respect for persons of diminished autonomy applies in such a way

that the less autonomy a subject possesses, the less suitable that

subject is for research, even if the research shows promise. The

Commission did not say to never involve persons with minimal or no

capacity to exercise autonomy, but to do so only as a last resort.

It is critical to recognize that an investigation of a promising

(but unproven) intervention is not carried out universally, i.e.,

studies are conducted in particular places. Similarly, although a

parent of a young child could argue that his or her child should not

have to wait for the trial in adults and older children to be completed

before having an opportunity to participate in research, the Commission

was not persuaded by that argument (although, in some cases, early

trials in young children might be carried out). The Commission did not

recognize the right of a needy person to gain access to a research

protocol. In choosing among sites for a clinical investigation, for

example, it is usual to select those in which the skills of

investigators and availability of subjects appear to predict an ability

to carry out the investigation successfully. Similarly, it is

reasonable to consider, in deciding where or in whom to conduct an

investigation, the ability of subjects to consent (or have consent

given for them). Widely accepted ethical principles indicate that a

decision to participate or not to participate in an investigation

should, if at all possible, be made by a competent subject who should

(as stated in the Nuremberg Code) be free of all force, fraud, fear, or

coercion. An exception from the requirement for informed consent should

be rare and narrow, confined to cases where consenting subjects are not

reasonably available. In addition, participation in the research must

hold out the prospect of direct benefit to the subjects and the

investigation must be one that is capable of providing useful

scientific/medical information.

If serving the interests of the subjects were considered sufficient

alone, that would imply that potential subjects have a right to

participate in the trial, an inappropriate consideration for an

investigational use and unrealistic, because studies cannot in fact be

carried out at all potential sites and in all patients.

The agency thus agrees with the comment that it is necessary for

there to be value to the subject from participating in the research;

but, given the general principle of obtaining informed consent where

possible, does not think that such potential benefit is sufficient

justification to include nonconsenting patients when it is reasonably

possible to conduct the clinical investigation in subjects who can

consent.

Therefore, if scientifically sound research can be practicably

carried out using only consenting subjects (directly, or in most cases

for the research contemplated in the rule, with legally authorized

representatives), then the agency thinks it should be carried out

without involving nonconsenting subjects. By practicable, the agency

means, for example, (1) That recruitment of consenting subjects does

not bias the science and the science is no less rigorous as a result of

restricting it to consenting subjects; or (2) that the research is not

unduly delayed by restricting it to consenting subjects.

6. Section 50.24(a)(5)(i)-(a)(5)(iii)--Community Consultation and

Public Disclosure

The greatest number of comments were received on

Sec. 50.24(a)(5)(i) through (a)(5)(iii), which have been renumbered

Sec. 50.24(a)(7)(i) through (a)(7)(iii) in this final rule in order to

have a more logical presentation of information. To assist readers,

these sections will be referred to as Sec. 50.24(a)(7)(i) through (iii)

in the discussion that follows. While most comments supported the

requirement for community consultation and public disclosure, many

requested clarification, offered suggestions, or concluded that

fulfilling these requirements would be impossible. Other comments

questioned whose responsibility it would be to disclose--the clinical

investigator, sponsor, or IRB. These comments are discussed in more

detail below.

60. A number of comments suggested alternatives to the requirement

for Sec. 50.24(a)(7)(i) for consultation with representatives of the

communities from which the subjects will be drawn. These included

limiting this provision to only those diseases for which a patient

advocacy organization exists; relying on the existing IRB mechanism

that already requires inclusion of an individual not otherwise

affiliated with the institution; requiring that IRB's have a community

member or an ad hoc community consultant who is intimately involved

with the projected research population; permitting an IRB to determine

that balanced community consultation is not feasible and documenting

and reporting

[[Page 51514]]

this determination to the sponsor and to FDA; increasing public

participation in the IRB process by specifying acceptable kinds of

individuals (e.g., clergy, local commissioners, police, paramedics) who

should be added to the IRB (limited to two); having the IRB membership

include individuals from the community groups from which subjects would

come and ensuring that the preferences of those members were followed;

establishing a standing community advisory board that would reflect the

diverse values and beliefs of the community. This board could serve

several IRB's within the same community. Another comment stressed that

the IRB must take into account the diverse religious and community

beliefs and attitudes about treatment of the dying and of research.

None of the suggested alternatives to Sec. 50.24(a)(7)(i) would by

themselves provide the protections of broad community consultation of

this section. While an IRB may appropriately decide to supplement its

members with consultants from the community, broader consultation with

the community is needed for this type of research. The agency expects

the IRB to provide an opportunity for the community from which research

subjects may be drawn to understand the proposed clinical investigation

and its risks and benefits and to discuss the investigation. The IRB

should consider this community discussion in reviewing the

investigation. Based on this community consultation, the IRB may

decide, among other things, that it is appropriate to attempt to

exclude certain groups from participation in the investigation; or that

wider community consultation and discussion is needed. As described in

the preamble to the proposed rule (60 FR 49086, September 21, 1995),

IRB's should consider, for example, having a public meeting in the

community to discuss the protocol; establishing a separate panel of

members of the community from which the subjects will be drawn;

including consultants to the IRB from the community from which the

subjects will be drawn; enhancing the membership of the IRB by adding

members who are not affiliated with the institution and are

representative of the community; or developing other mechanisms to

ensure community involvement and input into the IRB's decisionmaking

process. It is likely that multiple methods may be needed in order to

provide the supplemental information that the IRB will need from the

community to review this research.

61. Another comment noted that tribal approval and not just

consultation should be required and suggested that for American Indian/

Alaska Native tribal governments, the regulation require approval by

the tribal government for all research done within its jurisdiction.

This comment suggested that the regulation permit a recognized

government of the political community to disapprove research.

This regulation does not restrict or have an impact on any existing

authority of tribal governments to review and approve or disapprove

research that would otherwise be conducted on persons residing in

tribal jurisdictional boundaries. If existing tribal authorities

require tribal government approval of such research before it proceeds,

then the tribal governments continue to have that authority. Thus, the

agency thinks that adopting this suggestion is unnecessary.

62. Comments opposed to the community consultation required in

Sec. 50.24(a)(7)(i) suggested that the current requirement for a

community representative on the IRB (56.107(a)) was adequate; that this

would be burdensome for noncommercially sponsored studies; that it was

an insurmountable goal and that there is no guarantee that an IRB could

reach all impacted individuals. Other comments suggested that only a

central agency such as FDA or the Public Health Service should decide

because the clinical investigator will bias the outreach meetings to a

disinterested community that would be unable to make knowledgeable

decisions, and the community will be biased because the research would

bring funding support to the community, and because it is difficult to

define the community, especially for those institutions that receive

patients from a large region or State. A number of comments suggested

that community consultation could lead to IRB liability on the basis of

failure to solicit adequate community participation in the decision

process. Other comments noted that disclosure to the community does not

substitute for consent and that unless one included information about

the subject's right to refuse and how to exercise that right, community

consultation would be inadequate.

As discussed previously, the agency does not think that the current

IRB membership requirements adequately substitute for the community

consultation called for in this rule. The agency thinks that community

consultation provides a very important protection for research subjects

and, therefore, every effort should be made by the IRB to involve, and

consult with, the community from which research subjects may be drawn.

63. Other comments stated that without clear definition of terms,

the vagueness of the requirement would lead to inadequate consultation

and disclosure. Another comment noted that if minority or lower income

populations were unlikely to agree to the research and they represented

a large proportion of the potential research population, then the

conduct of the research would violate the principle of justice because

these populations would not share in its benefits or burdens.

The agency thinks that IRB's will ensure, through their review and

oversight activities, adequate consultation and disclosure. It is

impossible, without conscription, to ensure that each subpopulation

shares both the benefits or burdens of all research. Achieving the

principle of justice is a goal that must be balanced by other

principles. In the case of a population that is unwilling to agree to

participation in a research activity, honoring this population's

unwillingness is, in effect, permitting the community to express its

views.

64. A number of comments requested clarification of this

requirement. These comments asked how the consultation should take

place (newspaper, institutional newsletter, advertisement, local radio

stations, meeting); who in the community needs to be informed and who

may be legitimate representatives of the community; what the IRB does

with the community response (e.g., can a community veto research, what

if a small or a large number oppose the research, what is the sponsor

or IRB's responsibility to respond to questions or requested changes in

the research); how is an IRB to assess the effectiveness of the

consultation (e.g., if there is a poor turnout at an adequately

publicized meeting, is the IRB obliged to do more)? Another comment

requested clarification of what the public representatives and

representatives of the population at risk would be asked to do. One

comment urged the agency to refrain from providing precise definitions

for the various terms in Sec. 50.24(a)(7)(i) through (a)(7)(iii) in

order to permit IRB's adequate flexibility in making judgments.

Community consultation is likely to be multifaceted and to use a

number of the mechanisms suggested by the comments. As described

earlier, the IRB needs to provide an opportunity for broad community

discussion. If, for example, there is poor turn-out at a meeting to

discuss the research, an IRB may consider targeting specific

[[Page 51515]]

community representatives for inclusion in an additional meeting, or it

may decide that the research was not found by the community to be

objectionable. The IRB is responsible for listening and considering the

community's support, concerns, etc., and then ultimately deciding

whether the investigation should be modified, approved, or disapproved.

The community is expected to provide input to the IRB on its support

for or concerns about the research activity.

65. A number of comments requested clarification on who is

responsible for the community consultation and disclosure requirements

contained in Sec. 50.24(a)(7)(i) through (a)(7)(iii). Most comments

suggested that the IRB should be responsible for reviewing and

approving the content and method of consultation and disclosure; the

sponsor should be responsible for developing the plan for consultation

with the community and for disclosure and provide this information to

the IRB to review for adequacy.

Although a sponsor may provide to an IRB model information for use

in consultation with the community and for disclosure, just as it may

now provide a model consent form for a clinical investigation, it is

the responsibility of the IRB to ensure the adequacy of the community

consultation and disclosure requirements contained in

Sec. 50.24(a)(7)(i) and (a)(7)(ii).

66. Another comment recommended that the sponsor and clinical

investigator should pay for the costs associated with the disclosure

requirements.

The agency does not dictate the entity responsible for the costs

related to research. However, the agency anticipates that the sponsor

would normally incur the costs associated with disclosure to and

consultation with the community.

67. Several comments on Sec. 50.24(a)(7)(ii) suggested that for

multicenter trials, disclosure be required once for each metropolitan

area and that the disclosure be made by the sponsor or a designated

institution in a notice that would list all institutions,

investigators, and IRB contacts.

The agency would not object to such centralized disclosure if all

of the responsible IRB's agreed that this is appropriate and

acceptable.

68. Another comment suggested that instead of requiring disclosure

prior to the commencement of the study, disclosure occur at periodic

time intervals (e.g., every 2 years) and include a public notice of

general issues, specific projects, results of the research, and permit

public input.

It is the responsibility of the IRB to consider how to maintain the

flow of information to the community. In addition to requiring

disclosure to the community prior to the initiation of the clinical

investigation, the IRB may determine that it is appropriate to require

further disclosure at periodic intervals of time.

69. Another comment requested that the regulation specifically ban

``general disinformation campaigns'' by sponsors performing the

research.

The agency thinks that such a ban is unnecessary and that IRB

involvement in the disclosure process helps to eliminate the

possibility that biased or misleading information will be disseminated.

The information disseminated will be reviewed by the IRB to ensure its

adequacy and balance.

70. A number of comments were opposed to the requirements for

disclosure contained in Sec. 50.24(a)(7)(ii). The comments suggested

that they would take an exhaustive amount of time; could prevent

valuable research because the investigator and institution could be

targets of a poorly informed community; the investigator may not be the

best individual to discuss the study; they could cause persons to not

seek care; they would be burdensome for noncommercially sponsored

studies; for parties with an interest in the research, a requirement

for disclosure could lead to either a dishonest or incomplete

disclosure of information; the regulation requires disclosure of less

information than that which would be given to a research subject; that

it is essential to include information about financial and economic

incentives for the research; and that it is essential to permit public

participation in the disclosure sessions.

As discussed previously, it is the IRB's responsibility to

determine the information to be disclosed. As described in the preamble

to the proposed rule, the IRB should consider how best to publicly

disclose, prior to the commencement of the clinical investigation,

sufficient information to describe the investigation's risks and

benefits, e.g., relevant information from the investigator's brochure,

the informed consent document, and investigational protocol. Initial

disclosure of information will occur during the community consultation

process. Disclosure of this information to the community will inform

individuals within the community about the clinical investigation and

permit them to raise concerns and objections.

71. Another comment suggested that the release of confidential

information required by this section could serve as a disincentive for

sponsors to conduct the research and that it would create a precedent

that could affect companies not otherwise affected by the regulation.

The agency disagrees with this comment. While it is true that much

information relating to clinical investigations is normally treated as

confidential by sponsors, the agency believes that when a sponsor

chooses to invoke the exception from informed consent contained in this

rule that it is essential that reasonable disclosure occur to the

community. The agency believes that the benefit to a sponsor of

invoking the rule will outweigh concerns that a sponsor will have about

disclosing information about the investigation. Because this disclosure

is made only when the exception from informed consent is invoked, it

will not create any precedent for companies not invoking the exception.

The agency notes that sponsors release research information to

investigators and IRB's (for example, through the protocol and

investigators brochure) and to potential subjects in the research

through the informed consent process and informed consent form; this

rule states that the same information should be released to the

community so it can be informed as it considers the research.

FDA believes that American Indian and Alaska Native Tribal

governments and communities currently require both presentation of the

research protocol and reporting results to the community before they

permit any research to occur on their reservation. Recent Phase 2 and

Phase 3 trials of several vaccines (e.g., Haemophilus B, Hepatitis A,

and rotavirus vaccines) have been done on reservations under those

rules by the pharmaceutical companies sponsoring the research. Under

this rule, no company is required to release additional information to

a community if it does not want to have a waiver of consent for its

emergency research.

72. One of these comments stated that information is a property

right and to require that it be surrendered without compensation may

violate the Fifth Amendment of the Constitution.

The agency disagrees with this comment. The Fifth Amendment

requires that no private property be taken for a public purpose without

just compensation. (U.S. Constitution, Amendment V.) One factor used to

determine whether there has been a taking is whether the action

interferes with the reasonable investment backed expectations of the

owner of the alleged

[[Page 51516]]

property right. (Kaiser Aetna v. United States, 444 U.S. 164, 175

(1979).) Where a voluntary submitter of information is aware of the

conditions under which the information must be disclosed, the submitter

gains an economic advantage related to the submission (such as

registration), and the disclosure is rationally related to a legitimate

government interest, there is no taking. (Ruckelshaus v. Monsanto Co.,

467 U.S. 986, 1007-8 (1984).) Under this rule, the disclosure is

directly related to protecting the individual members of a community

that may be involved in the clinical investigation without informed

consent by providing the community with advance notice of the nature of

the investigation and the possibility that they may be involved in the

clinical investigation without their informed consent. Furthermore, the

regulation provides a mechanism under which the sponsor may perform the

clinical investigations and sets the conditions under which the

disclosure will occur. Therefore, the regulation serves as advance

notice that prevents a sponsor from having any reasonable investment-

backed expectation concerning the information and, thus, there is no

unconstitutional taking.

73. A number of comments raised questions about

Sec. 50.24(a)(7)(ii) including: what criteria would be used to

determine that disclosure was adequate; when is the disclosed

information to be provided to FDA; what is meant by ``sufficient'' and

``relevant''; whether it is sufficient prior to the study to simply

post a notice on the bulletin board; who determines the adequacy of the

disclosure; whether this places an obligation to ``disclose'' or to

``disseminate'' information to the community; what this disclosure is

supposed to accomplish. Clarification was requested as to the method

and scope of disclosure.

It is the responsibility of the IRB to determine the

``sufficiency'' of the information to be disclosed. The agency advises

that this information could include, but may not necessarily be limited

to, the information that is found in the informed consent document, the

investigator's brochure, and the research protocol. The obligation to

disclose information includes an obligation to disseminate information

to the community. The purposes of disclosure are to provide community

confidence in the role of the IRB and in its decisionmaking capability,

to permit the community to express its concerns and possible objections

to the research, and to inform the community so that it is aware that

the research is to be conducted involving individuals from the

community.

74. Another comment suggested that FDA and DHHS should provide

IRB's with copies of disclosure forms.

The agency disagrees. It is the IRB's responsibility to determine

the method for disclosure and information to be disclosed. A ``form''

would stifle IRB creativity and flexibility.

75. Comments on Sec. 50.24(a)(7)(iii) suggested that the regulation

specifically include the requirement that the underlying data be

disclosed following the end of the study; another suggested that

product approval decisions should be based on compliance with this

requirement as well as the timeliness of disclosure.

The agency does not think that these comments require a change in

the regulation. The agency thinks that it is necessary to provide

comprehensive summary data from the completed trial to the research

community in order to permit other researchers to assess the results of

the clinical investigation. The agency thinks that there must be a

scientific need to conduct clinical investigations involving subjects

who are unable to consent; if previous investigations have already

provided the scientific answer, this should be shared broadly with the

research community. Sufficient information may be contained in a

scientific publication of the results of the completed investigation;

in other instances, it may need to be supplemented by additional

information. The agency has modified Sec. 50.24(a)(7)(iii) to clarify

that the information to be disclosed is to include the demographic

characteristics (age, gender, and race) of the research population.

In response to the suggestion that product approval decisions

should be based on compliance with this requirement, the agency notes

that it has a variety of compliance procedures that it may use to

enforce this disclosure requirement.

76. Comments opposed to this disclosure requirement suggested that

it would jeopardize the ability to publish the results of the research

in peer review journals; it would foster unscientific conclusions

without peer review; an investigator cannot control the peer review

process to ensure publication; it could negatively influence future

trial recruitment and force a sponsor to disclose proprietary

information. Several comments suggested that in multicenter studies,

one institution may get a negative result, while another may get a

positive result; thus, disclosure could be misleading. Comments

suggested that updating the disclosure could be burdensome and that the

disclosure itself could be considered dissemination of off-label use

information and advertising. Another comment questioned the need for

such disclosure because the community would have no opportunity to

modify the research; another commented that the disclosure would be so

delayed and the community to which the disclosure would occur has such

insufficient knowledge to understand the disclosure, that the

disclosure would be meaningless.

Some comments requested that the agency define what and how

disclosure is to be accomplished; what is ``sufficient'' and what would

constitute the ``scientific community.'' One comment questioned whether

the information that would be disclosed to the community and

researchers would differ.

The comments opposed to this disclosure requirement illustrate a

need for the agency to clarify what is intended by this section. For a

multicenter investigation, the agency anticipates that the sponsor and/

or lead investigators will be responsible for analyzing the results of

the overall investigation, including the demographic characteristics of

the research population, and that these results will be published (or

reported in the lay press) within a reasonable period of time following

completion of the investigation. Publication in a scientific journal or

reports of the results by lay press, that would be supplemented upon

request by comprehensive summary data, will enable the research

community, e.g., researchers not connected to the clinical

investigation, to learn of the research's results. Following

publication, the IRB will be responsible for determining appropriate

mechanisms for providing this information, possibly supplemented by a

lay description, to the community from which research subjects were

drawn. The usual rules of marketing and promotion apply to the

disclosure of this information. The agency notes that it is common for

the results of research to be reported in the lay press and published

in peer reviewed journals.

77. One comment noted that the comment in the preamble that there

would be a need for fewer subjects if disclosure took place did not

recognize the possible need for replication of the research--a sound

scientific principle.

In the preamble to the proposed rule, the agency stated that:

``[b]y broadly sharing the results of the research with the scientific

community, there may be less need to replicate the research; therefore,

fewer subjects may be needed

[[Page 51517]]

to obtain the same level of scientific knowledge and to advance

emergency medicine.'' The agency recognizes that there is frequently a

need to replicate research in order to verify its findings. The agency

thinks, however, that broadly sharing both positive and negative

results of research with the scientific community may reduce or

eliminate unnecessary duplication of research that has been conducted

and verified by others.

7. Section 50.24(a)(5)(iv)--Data Monitoring Committees

A number of comments on proposed Sec. 50.24(a)(5)(iv), which has

been renumbered Sec. 50.24(a)(7)(iv) in this final rule, supported the

requirement for the establishment of an independent data monitoring

committee. These comments also requested clarification of the

requirement and offered various suggestions. A discussion of these

comments and the agency's response follows.

78. Editorial changes were suggested to this section to clarify the

function of the data monitoring committee.

The regulation has been changed to clarify that the purpose of the

data monitoring committee is to exercise oversight of the clinical

investigation. In addition, on the agency's own initiative, the agency

has changed ``data and safety monitoring board'' to ``independent data

monitoring committee'' to conform to wording used in the international

community.

79. Clarification was requested on the function, nature, authority,

and responsibility of the committee. One comment requested citations to

reference materials on data monitoring committees; another suggested

that the regulation reference FDA's ``Guideline for the Monitoring of

Clinical Investigations'' (53 FR 4723). One comment questioned whether

the committee was simply advisory or whether it would have authority to

halt a study. Other comments requested advice on the appropriate

composition of the committee and another requested that FDA define its

minimum size and expertise.

A number of comments requested clarification as to who is

responsible for establishing and operating the data monitoring

committee. One comment suggested that if it is the responsibility of

the sponsor to establish the committee, then the term ``independent''

needs to be defined. Several comments noted that if the responsibility

for establishing the committee changes, depending upon whether the

study is multicenter with a commercial sponsor or a single center,

noncommercially sponsored study, the circumstances for this shift in

responsibility must be clearly described. Another comment asked for

clarification as to who is responsible for establishing ``the

preestablished stopping rules'' and how these rules are defined.

Several comments suggested that it should be the responsibility of the

principal investigator and/or the sponsor of the research to convene

the committee. Another comment suggested that if it is the

responsibility of the sponsor to convene the committee for multicenter

studies, it should be explicitly stated in the regulations.

A number of suggestions were given for how the committee should be

composed and its functions. The agency also received suggestions for

alternatives to the establishment of such a committee. Several comments

suggested that the IRB be responsible for approving the composition of

the committee based on the complexity, size, and risks associated with

the study. Others suggested that the committee should be composed of

specific types of individuals, including scientists, community members,

IRB representatives without a conflict of interest, data management

representatives, biostatisticians, and noninvestigator clinicians.

Others suggested that a link be created between the committee and the

IRB and that specific reporting requirements between the two entities

be established so that the IRB can have the necessary information to

terminate or modify the study.

The agency recognizes that there is no clear consensus within the

scientific community regarding the optimal model for data monitoring

committees. It is not the intention of the agency to settle the debates

that are ongoing in the scientific community at this time. Rather, the

agency recognizes that there is diversity in this area; the role,

functions, and responsibilities of data monitoring committees are

evolving, and it may be the case that there is no single model that is

optimal in all circumstances. The data monitoring committee is

established by the sponsor of the research, as an advisory body to the

sponsor. An independent committee is constituted of individuals not

otherwise connected with the particular clinical investigation. A

variety of expertise is required for an effective data monitoring

committee. Typically included are clinicians specializing in the

relevant medical field(s), biostatisticians, and bioethicists. The data

monitoring committee receives study data on an ongoing basis on a

schedule generally defined in the investigational protocol; based on

its review of the data it may recommend to the sponsor that the

clinical investigation be modified or stopped. In effect, it is

responsible for making sure that continuing the investigation in its

current format remains appropriate, on both safety and scientific

grounds. A number of reasonable models for establishment and function

of these committees are described and discussed in S. Ellenberg, N.

Geller, R. Simon, S. Yusuf (editors), Practical issues in data

monitoring of clinical trials (Proceeding of an International Workshop)

Statistics in Medicine, vol. 12; 1993. If a sponsor accepts a data

monitoring committee's recommendation to stop the investigation or to

institute a major modification of the trial, the sponsor is required to

notify FDA and all participating investigators and IRB's in a written

IND or IDE safety report within 10 working days after the sponsor's

initial receipt of the information. (See Secs. 312.32, 312.56(d), and

812.150(b)(1)).

Protocols frequently contain statistical guidelines for permitting

trials to stop prior to completing the protocol-specified accrual and

followup, on the basis of definitive efficacy or safety differences

between the treatments being compared.

80. Comments opposed to this requirement mainly cited concern that

for single project/single institutional studies without a commercial

sponsor, the cost and resources required for establishing such a body

would be prohibitive and, therefore, important research would not be

done. Another comment suggested that for noncommercially funded

studies, the agency permit the investigator/sponsor to request a waiver

of the requirement to FDA. If such a waiver were granted, timely data

summaries could be submitted to FDA for review.

The agency disagrees with these comments. Trials of life-

threatening conditions may discover favorable or adverse effects on

survival during the trial. Requiring a data monitoring committee will

help ensure that if it becomes clear that the benefits of the

investigational intervention are established, or that risks are greater

than anticipated, or that the benefits do not justify the risks of the

research, the investigation can be modified to minimize those risks or

the clinical investigation can be halted. The data monitoring committee

is established by the sponsor of the research, as an advisory body to

the sponsor. It is the appropriate role of the sponsor, not FDA, to

receive and evaluate a data monitoring committee's

[[Page 51518]]

recommendation. The agency thinks that a data monitoring committee is a

very necessary protection for the human subjects participating in this

research. The agency thinks that the cost of operating such committees

does not need to be prohibitive and that the cost is justified by the

protections provided by having such a committee.

81. Others commented that the requirement for a data monitoring

committee is unnecessary given that these studies already will have

oversight by FDA and the IRB, both of which are independent of the

research, as well as by the sponsor and the clinical investigator.

The agency disagrees. The FDA, IRB, and research sponsor, unlike

the data monitoring committee, do not receive outcome data from the

clinical investigation on an ongoing basis. Thus, oversight by these

entities does not substitute for the requirement for a data monitoring

committee.

82. Another comment pointed out that there was no need for such a

committee for nondrug and nondevice studies if these involved no more

than minimal risk.

This regulation is applicable only to clinical investigations

involving products regulated by FDA.

83. One other comment suggested that this requirement would be

unduly burdensome unless the sponsor paid for the cost of establishing

and operating the committee (including paying for the salaries of

members on the committee).

As discussed previously, FDA does not prescribe what entity pays

for particular aspects of clinical research and review. However, if, as

previously described, the data monitoring committee is established by

the sponsor of the research as an advisory body to the sponsor, the

agency believes that it is likely that the sponsor will pay the cost of

establishing and operating the committee.

84. Another comment suggested that the make-up of the data

monitoring committee should not be left to the sponsor or clinical

investigator to decide and that ``independent'' should be defined as

``separate'' from the research team and sponsor. Another comment noted

that financial interest is only one aspect of what constitutes a

conflict of interest and that the preamble to the final rule should

clarify both terms when describing what constitutes an ``independent''

committee.

The agency believes that the 1993 Statistics in Medicine

publication of the proceedings of an international workshop (previously

referenced) will assist sponsors in establishing appropriate data

monitoring committees. As previously discussed, a variety of expertise

is required for an effective data monitoring committee; the agency

believes that it would be inappropriate for it to dictate the specific

make-up of each such committee. In the preamble to the proposed rule,

the agency defined ``independent'' to mean that the committee would be

composed solely of individuals who have no financial interest in the

outcome of the clinical investigation, and who have not been involved

in the design or conduct of the investigation. The agency does not

think that further clarification of ``independent'' is needed, but

other factors can certainly be taken into consideration in individual

cases.

85. One comment stated that the data monitoring committee should be

charged with monitoring the makeup of the study population to ensure

that it does not disproportionately consist of disadvantaged groups.

There is nothing to prevent a data monitoring committee from

performing this type of monitoring. It is the responsibility of the

sponsor to determine the scope of the data monitoring committee's

responsibilities.

86. Some comments suggested alternatives to requiring the creation

of a data monitoring committee, including requiring more frequent

continuing review by the IRB or permitting a sponsor's monitor to

perform the function. For noncommercially funded studies, it was

suggested that the agency permit the IRB, with scientific and

statistical consultants if needed, to perform the function.

An IRB, as well as a sponsor's monitor, may not have access to

study data on an ongoing basis and may not have the variety of

expertise required for an effective data monitoring committee. If an

IRB, a subcommittee of the IRB, or some other preexisting institutional

committee were to serve as a data monitoring committee, it would need

to be constituted as a data monitoring committee when it functions in

that capacity. The agency thinks that the duties and scope of

activities of an IRB and a data monitoring committee are quite

different and that it is important for separate entities to be

established. The agency would not object, however, to an already

established committee, such as an IRB, serving as a data monitoring

committee as long as that committee was constituted to perform the

duties of a data monitoring committee and operated as such separately

and distinctly from its IRB activities.

87. As described previously, the agency has added a new section,

Sec. 50.24(a)(7)(v), to provide an additional protection to research

subjects. This new section clarifies that if obtaining informed consent

is not feasible and if a legally authorized representative is not

available, the investigator will attempt to contact a family member of

the subject to determine whether the family member objects to the

subject's participation in the clinical investigation.

8. Section 50.24(a)(6)

88. Several comments were received on Sec. 50.24(a)(6). One comment

questioned whether the statement ``obtaining such consent may be

feasible for some subjects'' referred to a circumstance in which

obtaining consent may become feasible.

This comment did not take into account Sec. 50.24(b). Section

50.24(b) concerns providing information to the subject, representative,

or family member at the earliest feasible opportunity. Section

50.24(a)(6) is included to cover those instances where it may be

feasible to obtain informed consent from the individual subject or

subject's representative or contact a family member prior to entry into

the clinical investigation.

89. Two comments suggested specific wording changes to acknowledge

the IRB's responsibility to review informed consent procedures. One

suggested that this section be reworded to state:

The IRB has reviewed and approved informed consent procedures

and an informed consent document for subjects or their legal

representatives in situations where use of such procedures and

documents is feasible.

The agency has incorporated wording similar to that suggested into

the regulation. It is appropriate to recognize the informed consent

process, and not just the document, as requiring IRB review and

approval. In addition, in order to help ensure that the family member

has sufficient information to make a decision about a subject's

participation in a trial, the agency has added a sentence to the end of

Sec. 50.24(a)(6) that states ``[t]he IRB has reviewed and approved

procedures and information to be used when providing an opportunity for

a family member to object to a subject's participation in the clinical

investigation consistent with paragraph (a)(7)(v) of this section.''

The agency anticipates that these procedures and information will

likely parallel those approved by the IRB for use in obtaining informed

consent from subjects or their legally authorized representatives.

[[Page 51519]]

90. A second comment suggested that this section be replaced with

the following:

The IRB has reviewed and approved: (i) the informed consent

document and procedures to ask for informed consent by subjects or

legally authorized representatives when obtaining such consent may

be feasible for some subjects, (ii) the information provided and

process to ask for a decision by subject or legally authorized

representative to continue or discontinue participation after the

research has begun, (iii) the information provided and procedures

for consultation with representatives of the community, (iv) the

information provided and procedures for public disclosure before the

research, and (v) the information provided and procedures for public

disclosure of the results of the research. All documents and

procedures should also be submitted to the FDA for review.

This modification would require both the IRB and FDA to review and

approve all documents or procedures that give information to the

public, subjects, or representatives. The comment suggesting this

modification notes that this is currently required for all nonemergency

IND and IDE research.

The language suggested in this comment appears to duplicate

requirements already contained in the regulation, that is: the

requirement for review of informed consent documents is already

contained in Sec. 50.24(a)(6); the requirement for review of

information concerning the subject's ability to discontinue

participation in the research is contained in Sec. 50.24(b); and the

requirements for review of information used during consultation with or

disclosure to the community are contained in Sec. 50.24(a)(7)(i) to

(a)(7)(iii). FDA has confidence in the IRB review process and does not

think that it is necessary for all of these documents and procedures to

be submitted to FDA for its review. The agency notes that conforming

amendments to this regulation require that a copy of the information

publicly disclosed under Sec. 50.24(a)(7)(ii) and (a)(7)(iii) be

submitted to the IND or IDE file and to Dockets Management Branch. The

agency further notes that the statement that FDA currently requires all

of thes

This text is long and has been trimmed here. Open the source document for the complete record.