# Protection of Human Subjects; Informed Consent

> Briefs, arguments, decisions, and more.

URL: https://www.frixlaw.com/law-library/documents/fr%3A96-24967

## Record

- **Collection:** Federal Register
- **Document type:** Rule
- **Published:** October 2, 1996
- **Citation:** 61 FR 51498

## Text

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., clerg

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Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A96-24967. Public record. Not legal advice.