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Protection of Human Subjects; Informed Consent and Waiver of Informed Consent Requirements in Certain Emergency Research

WAIS Document Retrieval[Federal Register: October 2, 1996 (Volume 61, Number 192)]
[Rules and Regulations]
[Page 51497-51531]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr02oc96-21]

 

[[Page 51497]]

 


 

Part II

Department of Health and Human Services

 


 

Food and Drug Administration

Office of the Secretary

 


 

21 CFR Part 50, et al.

45 CFR Part 46

Protection of Human Subjects; Informed Consent and Waiver of Informed
Consent Requirements in Certain Emergency Research; Final Rules

[[Page 51498]]

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 50, 56, 312, 314, 601, 812, and 814

[Docket No. 95N-0158]
RIN 0910-AA60


Protection of Human Subjects; Informed Consent

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its current
informed consent regulations to permit harmonization of the Department
of Health and Human Services' (DHHS) policies on emergency research and
to reduce confusion on when such research can proceed without obtaining
an individual subject's informed consent. This regulation provides a
narrow exception to the requirement for obtaining and documenting
informed consent from each human subject, or his or her legally
authorized representative, prior to initiation of an experimental
intervention. The exception would apply to a limited class of research
activities involving human subjects who are in need of emergency
medical intervention but who cannot give informed consent because of
their life-threatening medical condition, and who do not have a legally
authorized person to represent them. FDA is taking this action in
response to growing concerns that current rules are making high quality
acute care research activities difficult or impossible to carry out at
a time when the need for such research is increasingly recognized.

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

FOR FURTHER INFORMATION CONTACT: Glen D. Drew, Office of Health Affairs
(HFY-20), Food and Drug Administration, Rockville, MD 20852, 301-443-
1382.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of September 21, 1995 (60 FR 49086), the
Secretary of Health and Human Services and the Commissioner of Food and
Drugs proposed to amend FDA's current informed consent regulations to
permit emergency care research. FDA proposed this action in response to
growing concerns that current rules are making high quality acute care
research activities difficult or impossible to carry out at a time when
the need for such research is increasingly recognized. By permitting
certain adequate and well-controlled clinical trials to occur that
involve human subjects who are confronted by a life-threatening
situation and who also are unable to give informed consent because of
their medical condition, the agency expects the clinical trials to
allow individuals in these situations access to potentially life-saving
therapies and to result in advancement in knowledge and improvement of
therapies used in emergency medical situations that currently have poor
clinical outcome.
FDA allowed 45 days for comment on the proposal of September 21,
1995. Written comments received in response to the proposal are on file
in the Dockets Management Branch. Comments were received from clinical
investigators, institutional review boards, patient advocacy groups,
trade associations, professional societies, drug and medical device
companies, and private citizens. The substantive comments received and
FDA's responses are discussed below.
Approximately 90 comments were received on the proposed rule. The
vast majority of these comments supported the proposal, although many
of these comments contained suggestions or requests for clarification.
A number of the comments that supported the proposal came from
organizations and associations representing large numbers of members.
These included the Brain Injury Association, the National Stroke
Association, the American Academy of Orthopaedic Surgeons, the
Coalition of Acute Resuscitation and Critical Care Researchers, Applied
Research Ethics National Association, Pharmaceutical Research and
Manufacturers of America, Health Industry Manufacturers Association
(HIMA), the American Academy of Pediatrics, the American Heart
Association Emergency Cardiac Care Committee, the American College of
Emergency Physicians, the American Medical Association, the American
College of Cardiology, the Society of Critical Care Medicine, the
National Association of EMS Physicians, the American College of
Obstetricians and Gynecology, and the American College of Physicians.
A number of the comments in favor of the proposal cited how it will
facilitate research in this patient population, provide the necessary
safeguards to ensure responsible and ethical research with protection
of the human subjects, and ultimately speed the wide availability of
products proven efficacious to individuals in life-threatening
situations. For example, the American College of Physicians and the
Project on Informed Consent of the University of Pennsylvania Center
for Bioethics commented that they ``applaud these proposed regulations
as a much needed step in the advancement of vital emergency research
with careful attention to the rights and welfare of human research
subjects.'' The American Heart Association commented that ``We are
particularly pleased with the balance that appears to have been struck
between the need for conducting high quality clinical research in an
effort to develop better treatments for critically ill patients and the
protection of human subjects.'' The American Medical Association
commented that ``The proposed rules are far superior to their
inadequate antecedents in balancing the need for emergency research
with respect for the paramount concern for patient safety, welfare and
comfort.'' The Brain Injury Association commented that ``* * * this
rule is a major step towards increasing the available therapies and
medical care available for those individuals who are critically ill or
injured.'' The Coalition of Acute Resuscitation and Critical Care
Researchers commented that ``* * * this proposed rule is a significant
step forward towards advancing the medical care of critically ill or
injured patients for whom current therapies are unsatisfactory or
unproven.'' The National Stoke Association commented that ``* * * once
in practice it will help to appropriately expedite study enrollments
thus allowing for earlier study completion, analysis, and ultimately
will speed the availability of those drugs proven efficacious to the
one-half million people who suffer stroke each year.''
These comments are addressed in more detail in sections II and III
of this document.
Generally, the 16 comments opposed to the proposed rule were from
individuals who were not convinced by the agency's description of the
legal and ethical basis for the rule, and these comments concluded that
informed consent should not be waived under any circumstances. Some of
these comments suggested that the agency was proceeding hastily and
under undue pressure from the research community. In section II of this
document, we address the general comments first, followed by the more
specific comments.

II. General Comments

A. Need for the Rule

1. One comment questioned the need for the rule and whether there
were hard data documenting the number of

[[Page 51499]]

subjects eligible for these types of research activities who are lost
to enrollment due to an inability to obtain informed consent from the
subject or the subject's authorized representative. Another comment
questioned the need for this rule based on the DHHS waiver granted in
July 1995 for a hypothermia study, arguing that: (1) The waiver was not
needed to complete a reasonable preliminary sample, (2) the criteria
for participation were needlessly inclusive, (3) the investigator used
questionable tactics to achieve waiver, (4) the provisions for
oversight were inadequate, and (5) the provisions for monitoring were
inadequate. This comment went on to discuss ``the overarching
considerations'' for the rule, arguing that it is not in the subject's
interest to prevent death in order to linger in a vegetative state;
that the high percentage of families agreeing to continuing
participation in the research after the fact demonstrates how ill-
informed they are about the possibility of negative outcomes, e.g.,
prolonged vegetative state, dissipation of financial resources, court
challenges to terminate life support; that subjects will be misenrolled
in ``an abundance'' of life-threatening situations; that the rule does
not address or provide for followup or special circumstances for
terminating life support for ``saved'' individuals in these studies;
and that it is not clear who will bear the cost and burden to sustain
an individual who has been ``saved'' from a life-threatening medical
condition by being on a research study.
The preamble to the proposed rule extensively discussed why this
rule is needed and why this limited class of research has been unable
to proceed under existing requirements. The purpose of this rule is to
permit the study of potential improvements in the treatment of life-
threatening conditions where current treatment is unproven or
unsatisfactory, in order to improve interventions and patient outcomes.
It is not the goal of this rule to leave study subjects in vegetative
states or to have any of the other negative outcomes outlined in the
comments. The risks to patients of having these negative outcomes exist
now with interventions that are unproven or unsatisfactory. If
interventions are improved, patient outcomes will be improved. The
possibility of worsened outcome or adverse reactions will be assessed
before the clinical investigation begins by the IRB and during the
investigation by the data monitoring committee that is required under
the regulation. The regulations require the institutional review board
(IRB) to ensure that risks to subjects are minimized and to determine
that risks to subjects are reasonable in relation to anticipated
benefits to subjects (see Sec. 56.111(a)(1) and (a)(2) (21 CFR
56.111(a)(1) and (a)(2)), respectively). The rule does not address the
issue of terminating life support because this is dictated by State law
and is implemented through such standard procedures as ``do not
resuscitate'' orders.

B. Ethical Objections to the Rule

2. Several objections to the proposed rule noted that the major
protection from research risks remains informed consent and that
without this procedure, potential abuse of research subjects will
always remain unacceptably high; that it is unethical for patients who
cannot consent to receive nonstandard care; that overriding individual
autonomy and not obtaining informed consent is unacceptable; that
therapeutic intent is not sufficient to obviate consent when there are
no data or when there is uncertainty or disagreement. Some of these
comments mentioned the recent report of the President's Advisory
Committee on Human Radiation Experiments, in which radiation
experiments without the subjects' consent are condemned as a wrongful
use of persons as means to the ends of others; others mentioned
examples from Nazi Germany, Stalin's U.S.S.R. and other totalitarian
regimes. Some of these comments noted that it is particularly
objectionable that there is no way to avoid involvement as a subject in
this research if, as an individual, one objects to the research.
The agency acknowledges that the waiver of informed consent is a
serious matter. That is why it has developed a regulation that requires
additional protections when informed consent is waived. The purpose of
this rule is to ensure such protections.
The National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research states in The Belmont Report that:

Respect for persons incorporates at least two basic ethical
convictions: first, that individuals should be treated as autonomous
agents, and second, that persons with diminished autonomy are
entitled to protection. The principle of respect for persons thus
divides into two separate moral requirements: the requirement to
acknowledge autonomy and the requirement to protect those with
diminished autonomy.

This rule, Sec. 50.24 (21 CFR 50.24) in part 50 (21 CFR part 50), can
be invoked for emergency research in which it is not feasible to obtain
informed consent from prospective subjects. As such, these subjects
have diminished autonomy and are entitled to protection. The Belmont
Report states that:

The extent of protection afforded [to individuals with
diminished autonomy] should depend upon the risk of harm and the
likelihood of benefit. The judgment that any individual lacks
autonomy should be periodically reevaluated and will vary in
different situations.

The Belmont Report, thus, states that: (1) Subjects with diminished
autonomy are entitled to protection; (2) the extent of protection
should depend upon the risk of harm and the likelihood of benefit; and
(3) the judgment that any individual lacks autonomy should be
periodically reevaluated. This regulation incorporates each of these
principles.
The regulation recognizes that subjects with diminished autonomy
are entitled to protection. These additional protections include the
requirements in the regulation for consultation with representatives of
the communities from which the subjects will be drawn; public
disclosure of the clinical investigation and its risks and expected
benefits prior to initiation of the investigation; public disclosure of
sufficient information following completion of the investigation to
apprise the community and researchers of the results of the
investigation; the establishment of a data monitoring committee to
exercise oversight of the investigation; and, if consent is not
feasible and a legally authorized representative is not available,
providing an opportunity for a family member to object to a subject's
participation in the investigation, if feasible within the therapeutic
window.
The regulation recognizes that the extent of protection should
depend upon the risk of harm and the likelihood of benefit to the
subjects. The regulation requires the IRB to find and document that
appropriate animal and other preclinical studies have been conducted;
that the information derived from those studies and related evidence
support the potential of providing a direct benefit to the individual
subjects; and that the risks associated with the investigation are
reasonable in the light of what is known about the prospective
subjects' medical condition, the risks and benefits of standard
therapy, if any, and what is known about the risks and benefits of the
proposed intervention or activity.
The regulation recognizes that the judgment that any individual
lacks autonomy should be periodically reevaluated. This is reflected in
two requirements: (1) The IRB must review and approve informed consent

[[Page 51500]]

procedures and an informed consent document for use with subjects or
their legal representatives in situations where use of such procedures
and documents is feasible; and (2) at the earliest feasible
opportunity, each subject (or a legally authorized representative or
family member) will be informed of the subject's inclusion in the
research, the details of the research, and that the subject (or
representative or family member) may discontinue the subject's
participation at any time without penalty or loss of benefits to which
the subject is otherwise entitled.
In response to the comments that expressed concern about the
ability of an individual to avoid involvement as a subject in this
research, the agency thinks that the opportunity for individuals to
express objections to the research may be optimized in a number of
ways. Comments suggested making available medical bracelets that record
refusal to participate in the research, and publicizing the existence
of the bracelets; and excluding from participation those individuals
with advance directives rejecting such research (most feasible for
hospitalized patients). The agency encourages IRB's, investigators, and
sponsors to work together to maximize the ability of individuals to
prevent their inclusion in research to which they would object. The
agency does not believe that this rule creates a situation that differs
significantly from other emergency situations warranting intervention
in that individuals in life-threatening situations are often unable to
direct decisions concerning their health care and are, therefore,
unable to consent or object to a particular treatment. Yet they are
routinely treated by State-licensed medical practitioners. This
inability to exercise autonomy is not unique to the subjects who will
be eligible for this research--it is common to the majority of
individuals who may be in these life-threatening situations.
FDA thinks that the protections contained in this rule including
IRB review, the requirements for obtaining informed consent when it is
feasible, and for community consultation and disclosure will prevent
unethical research from occurring.
FDA expects these procedures involving waiver of informed consent
to be used infrequently. As noted, the research carried out under such
a waiver must present the potential of direct benefit to the individual
subjects. It should be initiated only after appropriate animal and
other preclinical studies have been conducted, and it is clear that the
information derived from those studies and related evidence support the
potential of direct benefit to the individual subjects.
3. One comment stated that the proposal violates the American
Hospital Association's ``Patient's Bill of Rights'' to fully informed
consent.
The agency has reviewed the AHA's Patient's Bill of Rights and
concludes that there is no conflict between this rule and that
document. In particular, the agency notes that the Patient's Bill of
Rights recognizes that an exception occurs ``in emergencies when the
patient lacks decision-making capacity and the need for treatment is
urgent.''
4. Another comment questioned the agency's discussion of respect
for persons in the preamble to the proposal and the agency's supposed
conclusion that if individuals capable of exercising their autonomy
refuse to enroll in research, this justifies diminished protection to
those individuals who lack the capacity for autonomous choice. This
comment defined the informed consent doctrine as: (1) Promoting
individual autonomy; (2) respecting human dignity; (3) encouraging
professional self-scrutiny; (4) promoting rational decisionmaking; (5)
avoiding deceit and coercion; and (6) educating the public. It then
concluded, that by exempting emergency research from informed consent,
the agency was concluding that these values have no relevance to
decisions made in the context of emergency research.
This comment misrepresents the agency's discussion of the principle
of respect for persons. In the preamble to the proposed rule, the
agency described:

[H]ow the principle of respect for persons incorporates two
general rules of ethical behavior: (1) Competent individuals must be
treated as autonomous agents * * *; and (2) persons whose autonomy
is absent or diminished may participate in research only if
additional protections are provided for them.

(60 FR 49086 at 49093, September 21, 1995)
This rule, in fact, incorporates the values described in the comment to
the extent that they are relevant to decisions made in the context of
emergency research.
5. A number of comments misinterpreted the agency's description of
the principle of justice in the preamble to the proposed rule, and were
offended by the idea that it is acceptable for a researcher to waive
consent because if consent were requested, it would be refused. One
comment suggested that the agency clarify that it meant that it is
often easier to locate legal representatives from white populations
than from minority populations, and for that reason if consent were
required from a legally authorized representative, the requirement
could prevent equitable numbers of minority patients from having the
opportunity to participate in emergency research. The Indian Health
Service recommended that the agency supplement its discussion of
justice by adding the following:

Waiving informed consent will increase justice only in
communities or sub-communities with a low percentage of people who
would refuse to participate if asked. Many minority or economically
disadvantaged communities distrust research more, and have higher
percentages of refusers, than white middle class communities; in
such communities, the ethical principle of justice would favor
maximizing self-determination (i.e., informed consent) over
achieving high rates of participation. Justice would also require
the public disclosure to and consultation with those communities as
required in the Proposed Rule; if those communities do not agree to
be sites, consideration should be given to doing the research
elsewhere.

The Indian Health Service, in supporting the intent of the rule,
articulated two aspects of the problem: (1) Finding legally qualified
surrogates for individuals who lack telephones, for example, which is a
socioeconomic barrier; and (2) a surrogate's unwillingness to enroll a
relative in the research, based on distrust of research and
researchers. If certain communities have a higher prevalence of
refusers than others, the ethical harm of inadvertently enrolling
people in research against their will would fall on those communities
with a higher prevalence of refusers. Thus, the Indian Health Service
(IHS) concluded that while it may be appropriate to waive informed
consent based on socioeconomic barriers, it is not appropriate to waive
informed consent in communities in which there are lower rates of
obtaining surrogate consent due to the unwillingness of surrogates,
i.e., high refusal rates. Another comment noted that if the community
in which an emergency research study is carried out has a large
minority and lower income population, then the likelihood of the
community agreeing prospectively to participate in the study would be
small or nonexistent; ethically this would violate the principle of
justice in that such communities would be unlikely to share the burdens
and benefits of participation in such research.
The agency's comments concerning justice, in the preamble to the
proposed rule, concerned the ability of health care delivery personnel
to locate legally authorized representatives. The agency agrees with
the IHS articulation of the

[[Page 51501]]

two aspects of the problem. The agency would not consider writing a
rule that would permit the waiver of informed consent in a situation
where if consent were requested, it would be refused. Such an action
would violate ethical principles.
The agency has implicitly addressed the problem of a surrogate's
unwillingness to enroll a relative in research through the rule's
requirement for community involvement, including consultation with and
disclosure to the community, and by providing that consent from the
subject or the subject's legally authorized representative be obtained
or an opportunity for a family member to object be provided when it is
feasible.
If an IRB decides that its community should not participate in
research, the agency does not believe that decision would violate the
principle of justice. Justice, in this context, requires only that the
community have the opportunity to participate in the research if asked.

C. Harmonization

6. A number of comments applauded the intent of FDA and DHHS to
harmonize regulations in this area. Concern was expressed, however,
that because FDA and DHHS did not propose regulations simultaneously,
the two regulations may not ultimately be identical, thus thwarting a
major objective of this endeavor. One comment expressed concern that
the DHHS waiver might follow the specific project waiver for
hypothermia research that was published in July 1995, that, according
to the comment, was not sufficiently protective of subject rights.
Another comment suggested that for studies that do not involve drugs or
devices, DHHS develop an analogous mechanism to FDA's requirement that
studies be submitted for agency review. Another comment suggested that
the two sets of regulations not be in total harmony in this regard,
because a greater degree of protection of subjects is necessary for
studies of drugs and devices that are not yet FDA-approved, than for
those involving drugs or devices that have received approval. One
comment encouraged FDA and the Office for Protection from Research
Risks (OPRR) to work together to ensure that current Multiple Project
Assurances remain valid and not require renegotiation as a result of
this rule.
DHHS has committed to consistency between the FDA final rule and
the Secretarial waiver of the DHHS regulations in all critical
respects. Elsewhere in this issue of the Federal Register is the
Secretarial waiver of the DHHS regulations for the protection of
research subjects for emergency research. The agency notes that FDA's
rule requires investigational new drug applications (IND's) and
investigational device exemptions (IDE's) for all clinical
investigations involving drugs and devices seeking an exception to the
requirement for informed consent, including both those that have
received marketing approval and those that have not.
7. Other comments asked for clarification as to whether the
requirement contained in Sec. 50.24(d) would apply to studies that
attempt to elucidate a pathophysiologic explanation (e.g., blood
drawing studies); studies that use interventions of different
techniques (e.g., two different methods of bystander CPR); research
designed to explore basic pathophysiological mechanisms in emergency
situations; studies to compare the timing of standard fluid
administration for shock and surgical techniques; etc. If FDA's
regulation did not apply, these comments asked if the DHHS
``harmonized'' regulation would apply to these studies and require
prior DHHS review or whether some other agency would be responsible for
prior review of the proposed research.
These regulations are applicable only to clinical investigations
involving products that are regulated by FDA. The DHHS regulations
apply to research supported or conducted by the Department or conducted
in an institution that has agreed to review all research, regardless of
its funding source, in accord with the DHHS regulations. The
``harmonized'' regulations have compatible criteria; their basic
requirements are in agreement. FDA includes terms specific to the type
of research covered by FDA regulations (e.g., it uses the term clinical
investigation instead of research). Both the DHHS and FDA recognize
that there may be research that is neither regulated by FDA nor
supported or conducted by DHHS; for that research, it is possible that
neither regulation will apply.

D. Comment Period and Effective Date

Several comments opposed to the regulation objected to the 45-day
comment period and the agency's proposal that the final rule will be
effective upon publication.
8. One comment suggested that the effective date of the regulations
should be 30 days after publication of the final rule. This comment
noted that this research has been halted since mid-1993, that all
parties will need time to develop adequate policies and procedures to
comply with the new rule, and that distribution of the policy to those
affected will take up to 30 days.
The agency agrees with this comment and has made the effective date
of the final rule 30 days after its publication in the Federal
Register. The agency notes that the Secretarial waiver of the DHHS
regulations, published elsewhere in this Federal Register, is also
effective 30 days after its publication. IND's and IDE's that intend to
invoke this rule may be submitted to the agency on or after its
publication date and should include a description of how the clinical
investigation proposes to meet the conditions of this regulation. These
investigations cannot begin until the rule is effective, the agency has
reviewed the investigation against the requirements contained in this
final rule, a letter has issued to the sponsor advising the sponsor
that the investigation may proceed, the investigation has been reviewed
and approved by an IRB, and the community consultation and disclosure
required by this rule have occurred.
9. Comments objecting to the 45-day comment period suggested that
there was inadequate time to discuss the proposed changes in the
regulation at length with a broader audience, that the IRB community is
ill-informed about the proposed rule change and therefore the comment
period should be extended, the issue revisited, and the rule
reconsidered. One of these comments stated that the process leading to
development of the rule was flawed and that it appears that the comment
period is irrelevant, that no significant review of the basic issues
will occur, and, thus, the rule is a fait accompli.
As described in detail in the preamble to the proposed rule, the
issues associated with this rule were debated at length at conferences,
during FDA and NIH cosponsored Public Forum on Informed Consent in
Clinical Research Conducted in Emergency Circumstances, at a
congressional hearing, and in various articles. The agency received no
formal request for a general extension of the comment period; instead,
it received numerous thoughtful comments and has modified the proposed
rule as a result of those comments. 21 CFR 10.40(b)(2) states that a
proposed rule ``* * * will provide 60 days for comment, although the
Commissioner may shorten or lengthen this time period for good cause.
In no event is the time for comment to be less than 10 days.'' In the
proposed rule, the agency explained why the Commissioner determined
that there was good cause to shorten the comment period from 60 to 45
days.

[[Page 51502]]

In order to encourage comments on this rule, the agency conducted a
number of out-reach efforts to publicize publication of the proposal.
The agency provided information on the proposed rule to national media
and trade press contacts. The agency mailed copies of the proposal to
all registrants at the January 1995 Public Forum on Informed Consent in
Clinical Research Conducted in Emergency Circumstances and to over
1,000 IRB's and over 250 health professional organizations and consumer
groups. FDA also distributed copies at workshops and at national
meetings of IRB organizations. The agency invited consumer, health
professional, and industry organizations to briefing meetings where the
proposal was described and questions could be answered. The agency
encouraged the submission of comments to the administrative record
maintained by the Dockets Management Branch whenever possible.

E. Preemptive Effect

10. In the preamble to the proposed rule, FDA requested comment on
the need to preempt local and State regulations. The agency received a
number of comments both for and against the need for preemption.
Comments received that were opposed to preemption included the
following: There is no legitimate (constitutional) over-riding Federal
concern that requires the Federal Government to preempt local and State
requirements; it is inappropriate to remove the ability of citizens to
enact State and/or local laws that would require additional protections
for research subjects, or to restrict the conduct of this type of
research if citizens find it objectionable based on community
standards; it is not logical to prohibit local action when the
regulation itself emphasizes community involvement and deference to
community standards.
The IHS objected to Federal preemption because it would: (1)
Counter the long-standing Federal policy not to place restrictions on
tribal sovereignty; (2) be an unnecessary limitation, because retaining
tribal sovereignty would have no measurable adverse effect on the
nation or on emergency research as a whole; (3) give American Indian
and Alaska Native (AI/AN) people and governments one more reason to
distrust the Federal Government, because they would see the rule as
putting AI/AN people at risk for the good of non-AI/AN people and
communities; and give AI/AN people and governments one more reason to
distrust research, because they would see the rule as overriding a
patient's or family's desire not to participate in research--a desire
more common in AI/AN communities than in white middle class
communities.
Other comments noted that the proposal did not recognize tribal
sovereignty and that it undermines the tribal government's authority to
implement stricter requirements for biomedical research conducted on
persons residing in tribal jurisdictional boundaries. Comments noted
that the tribal review process is in place to protect tribal members
from unnecessary or undesirable research.
Another comment opposed to preemption noted that the rule would
preempt State and local laws for the minimum protections acceptable for
emergency research involving waiver of informed consent; however,
without preemption, it permits greater protections to be imposed at the
State or local levels. One comment suggested that in lieu of
preemption, FDA and IRB's should track how States, local, or tribal
governments retain or amend their laws in response to public discussion
by researchers with those governments and assess the various reactions
after 3 years.
Other comments supported the need for preemption in order to ensure
national uniformity; to prevent or limit liability of universities,
hospitals, IRB members, clinical investigators, and sponsors for
failure to provide informed consent under State law or in the event of
a poor subject outcome; and to enhance the ability to conduct valuable
research with critically ill subjects. These comments stated that the
subject protections included in the proposed regulation are substantial
enough to justify Federal preemption of State and local law, and that
current State laws (e.g., in the State of Florida) would preclude
research that otherwise could be authorized by IRB's under these rules.
Several comments supported the need for preemption, noting the
difficulty caused by differing State laws that define who may serve as
a legal representative or that are ambiguous on this issue. Another
comment noted that without Federal preemption, Federal uniformity in
the application of waiver of informed consent in a specific setting
will not occur. This comment argued that Federal preemption would: (1)
Forestall wasteful State court litigation to explore whether the scope
of the privilege of emergency action without consent is consistent with
the proposed Federal rule, and any related potential liability; and (2)
implement congressional intent to create nationally uniform criteria
for informed consent and research involving human subjects.
The Coalition of Acute Resuscitation and Critical Care Researchers
surveyed a number of State representatives regarding State regulations
for informed consent for research and identification of surrogates. The
results of that survey (with 19 States represented) indicate that there
are very few States that have specific legal requirements pertaining to
waiver of consent for research.
The agency has carefully considered each of these arguments in
support of, and opposed to, preemption of State law. The agency has
concluded that it would be inappropriate to preempt State law at this
time. Preemption of State law would prevent the application of State or
local law that requires additional protections to research subjects
and, as such, would be inconsistent with the existing Federal policy
for the Protection of Human Subjects and the DHHS regulations (45 CFR
46); in addition, it would be inconsistent with the notion of community
norms, upon which this regulation is based.

F. Followup/Reassessment

11. One comment recommended that the implementation of this rule be
assessed in 3 years and that any pending questions be addressed during
the assessment. Another comment asked the agency to announce its intent
to survey and analyze the experience with the rule following 3 years of
implementation. The comment recommended that the rule encourage IRB's
and researchers to track implementation information including: The
number of times the researcher was able to contact legally authorized
representatives within the allowed therapeutic window time period;
problems with the documentation and procedures used for the consent
process with those representatives; the percentage of subjects or
legally authorized representatives who wanted to discontinue the
intervention or to remove their data from the research database in the
posthoc debriefing; problems with documents and procedures used to give
the community the preresearch public information and the post-research
information; and problems with the documents and procedures for
consulting with community representatives. This comment suggested that
this information be described both as seen by the IRB and by the
experienced researcher.
The agency agrees that it will be important to assess
implementation of this rule and, thus, the agency intends to evaluate
implementation of this rule

[[Page 51503]]

on an ongoing basis. The agency believes that a sponsor's IND or IDE
and new drug application (NDA), product license application (PLA), or
premarket approval application (PMA) should contain sufficient
information under the agency's existing reporting and recordkeeping
requirements for the agency to assess how well this rule is working
without requiring additional information collection and recordkeeping
by researchers and IRB's of their experiences under the rule. The
agency, however, encourages IRB's, researchers, and sponsors to share
their experiences under this rule, for example, in publications and at
conferences, so that the research community and public can benefit from
their experiences. The agency notes that for research that is regulated
by FDA, although subjects, legally authorized representatives, or
family members may elect to withdraw from continued participation in
the clinical investigation, they may not remove previously collected
data from the research database because it is critical that FDA obtain
and be able to consider all data on a product's use in order to be able
to determine its safety and efficacy.

G. Scope/Applicability

1. Special Populations
12. One comment questioned the applicability of this rule to
specific special patient populations. This comment recommended that FDA
rule state that it does not apply to research involving prisoners or
fetuses; and urged that the decision about its applicability to
emergency research targeting pregnant women be made after the DHHS
regulations have been revised and the 3 year period in which experience
of implementing the rule will be obtained and analyzed. This comment
recommended that pregnant women should not be excluded from emergency
research. This comment also recommended that the rule state that it
does not apply to children now; rules for pediatric emergency research
should be developed by the end of the 3 year period of experience and
assessment; and noted that the process of Secretarial waiver is
available if an exception for a specific pediatric emergency protocol
must be made before then.
Taking a contrary view, the American Academy of Pediatrics stated
that:

* * * it is important that children be included in research
protocols, including those on emergency treatments, so that the
safety and efficacy of various treatment methods can be determined
in a scientific manner. We believe that this proposed regulation
will help to further that objective while protecting children as
much as possible by requiring that a consent document be available
in cases where surrogate permission can be obtained in a timely
manner.

The agency believes that it would be inappropriate to exclude any
special subject population from this regulation. Moreover, for research
regulated by FDA, a Secretarial waiver of the informed consent
requirement may not be an option. Thus, the agency is not limiting the
applicability of this regulation to exclude any special subject
population. The agency notes that it is the general responsibility of
the IRB, where some or all of the subjects are likely to be vulnerable
to coercion or undue influence, to ensure that appropriate additional
safeguards have been included in the clinical investigation to protect
the rights and welfare of these subjects. (See 21 CFR 56.111(b).) The
subject population covered in this rule is, in a sense, a particularly
vulnerable population, by having no capacity to decide about medical
treatments. The additional safeguards in the rule are included for this
reason.
2. Existing Regulations
13. One comment asked the agency and DHHS, respectively, to
explicitly state, when this rule is finalized, that FDA will retain
Sec. 50.23(a) (21 CFR 50.23(a)) and the DHHS will retain 45 CFR
46.116(d).
Both FDA and DHHS will retain these sections in the Code of Federal
Regulations. These sections will continue to be useful in situations
not otherwise covered by this regulation.
14. Another comment suggested that the regulations address
compensation or medical treatment available in the event of
unanticipated injuries or death.
The agency agrees that it is important for all subjects in a
clinical investigation to be provided with the basic information
required by Sec. 50.25, including Sec. 50.25(a)(6) that requires that
information be provided to each subject about whether any compensation
and any medical treatments are available if injury occurs and, if so,
what they consist of, or where further information may be obtained. As
a result, the agency has modified Sec. 50.24(a)(6), previously numbered
Sec. 50.24(a)(5), to make it clear that the IRB-approved informed
consent document must be consistent with Sec. 50.25. The agency has
also modified Sec. 50.24(b) to make it clear that when prospective
informed consent cannot be obtained, the subject, or the subject's
legally authorized representative or family member is to be informed,
at the earliest feasible opportunity, of the subject's inclusion in the
clinical investigation, the details of the investigation, and other
information contained in the informed consent document.
15. A third comment requested the agency to retain two protections
previously established by the agency that are not contained in the
proposed rule: (1) That the intervention be in the health interest of
the subjects; and (2) that an attempt to obtain informed consent be
made and documented for enrolled research subjects by a physician
unaffiliated with the research activity.
The agency thinks that the concerns expressed by the first
protection are addressed in Sec. 50.24(a)(3), which requires that
participation in the research hold out the prospect of direct benefit
to the subjects. The second protection is similar to that contained in
Sec. 50.23(a), which requires, in effect, a second opinion from a
physician who is not otherwise participating in the clinical
investigation that the conditions for waiving informed consent are met.
This protection is performed for the class of subjects in this research
by the requirement in Sec. 50.24(a)(2) that a determination be made
that obtaining informed consent is not feasible and that this
determination receive the concurrence of a licensed physician who is
either an IRB member or a consultant to the IRB, and who is not
otherwise participating in the clinical investigation (Sec. 50.24(a)).
The agency notes that Sec. 50.24(b) requires that at the earliest
feasible opportunity, each subject is to be informed of the subject's
inclusion in the clinical investigation, the details of the
investigation and other information contained in the informed consent
document. The agency also notes that under new Sec. 50.24(a)(5), the
researcher is required to describe the efforts made to obtain informed
consent and make this information available to the IRB at the time of
continuing review.
3. Foreign Data
16. One comment noted that the rule was silent as to its potential
impact on the acceptability of data generated in emergency research
studies that are not subject to the proposed rule--i.e., studies
conducted outside the United States and outside the scope of the IND
and IDE regulations. This comment asked FDA to make it clear that such
studies will continue to be considered acceptable in terms of providing
evidence of safety and effectiveness and could be treated as pivotal
trials, even though they may not meet some of the proposed requirements
for the conduct

[[Page 51504]]

of emergency research. This comment stated that if this clarification
is not consistent with the agency's intent, then the proposal
effectively establishes a new, inappropriate standard concerning the
adequacy of clinical studies for purposes of providing evidence of
safety and effectiveness that would require specific notice-and-comment
rulemaking.
Sections 312.120 and 814.15 (21 CFR 312.120 and 814.15) describe
the criteria for acceptance by FDA of foreign clinical investigations
not conducted under an IND and IDE, respectively. In general, FDA
accepts such clinical investigations provided they are well designed,
well conducted, performed by qualified investigators, and conducted in
accordance with ethical principles acceptable to the world community.
FDA will accept such emergency research investigations provided that
they meet the requirements of Sec. 312.120 and Sec. 814.15. This rule
does not change the requirements of Sec. 312.120 and Sec. 814.15.
17. One comment noted that the International Conference on
Harmonisation Draft Guideline on Good Clinical Practice (GCP) (60 FR
42948, August 17, 1995) states that ``the rights, safety, and well-
being of the trial subjects are the most important considerations and
should prevail over [the] interests of science and society.'' This
comment suggested that the main argument for the proposed rule is for
the benefit that the new drugs and devices will bring to science and
society, rather then recognizing, as the GCP does, the value of the
individual and subject rights.
The agency disagrees that this rule is inconsistent with the ICH
Draft Guideline and has emphasized in the preamble to this regulation
that the basic rationale for this rule is that it holds out the
prospect of direct benefit to the subjects. The agency is committed to
protecting the rights of research subjects. In addition, FDA recognizes
that this rule may also serve society by making available more drugs
and devices for use in emergency, life-threatening situations. The
agency notes that the draft GCP cited specifically acknowledges the
need for waivers of informed consent in some circumstances.
4. Independent IRB's
18. One comment expressed concern about FDA's continued acceptance
of reviews by ``independent'' IRB's. This comment questioned the
ability of a nonlocal, independent IRB to have local insight and
knowledge necessary for comprehensive review and continuing oversight,
and suggested that unless there is monitoring of independent IRB's by
OPRR, they should not be allowed to approve research under this rule.
The agency received other comments asserting that independent IRB's are
well-qualified to maintain the requisite oversight and responsibilities
of emergency research trials and that independent IRB's can maintain
ethical standards equivalent to dependent IRB's.
As previously discussed in the preamble to the proposed rule, the
agency thinks that independent IRB's can properly review this type of
research. The agency thinks that duly constituted IRB's can ensure that
the rights and welfare of research subjects are protected by fulfilling
the requirements of part 56 (21 CFR part 56) and Sec. 50.24, including
Sec. 50.24(a)(7) requiring public disclosure as well as consultation
with the communities from which the subjects will be drawn. FDA
anticipates that this type of research will usually be performed in an
institution with an IRB. In that case, the IRB for the institution has
the responsibility and authority to review all studies performed in the
institution. This review responsibility may not be delegated to another
IRB unless the institution and the IRB for the institution agree to the
delegation and the agreement is documented in writing.
5. Conflicts with Statutes, the Constitution, and Other Standards
19. One comment stated that the rule conflicts with State common
law--that is, a physician who performs research without obtaining
consent for that research will be liable under common law for
malpractice and battery, and is likely to lose his or her license. This
comment stated that by adopting the proposed rule, FDA is overstepping
its authority by attempting to regulate the practice of medicine and by
attempting to override State law, and that FDA lacks the authority to
permit anyone in the medical profession to practice without obtaining
consent.
FDA disagrees with the comment. This rule does not attempt to
regulate the practice of medicine. Rather, as discussed more fully in
the preamble to the proposed rule, FDA is regulating investigational
products under the statutory authority contained in the Federal Food,
Drug, and Cosmetic Act (the act). FDA also disagrees with the comment
that FDA is overriding State law. As stated elsewhere in this preamble,
FDA is not changing the existing Federal policy that recognizes the
continuing validity of applicable State or local laws and regulations
on human subject protections. With regard to physician liability for
performing research under this regulation, FDA disagrees with the
comment's blanket conclusion that physicians participating in such
research are committing malpractice and battery. FDA notes that this
rule does not override existing State and local laws and regulations
that may apply to such research. Institutions wishing to participate in
such research may wish to consult their attorneys regarding any State
and local restrictions that preclude such research. As with other
research, physician liability for activities engaged in during
emergency research will vary from State to State because of different
laws on human subject protections. FDA notes that an existing
regulation Sec. 50.23 permits waiver of informed consent in certain
limited emergency situations. FDA is unaware of any research conducted
in accordance with that regulation that has resulted in physician
liability for malpractice or battery.
20. One comment stated that the proposal violates Federal law under
the Patient Self-Determination Act of 1990.
FDA disagrees with the comment. The Patient Self-Determination Act
of 1990 defines an advance directive as ``a written instruction, such
as a living will or durable power of attorney for health care,
recognized under State law (whether statutory or as recognized by the
courts of the State) and relating to the provision of such care when
the individual is incapacitated.'' (42 U.S.C. 1395cc(f)(3).) That act
imposes obligations on certain facilities (hospitals, skilled nursing
homes, home health agencies, and hospice programs) participating in the
Medicare program regarding advance directives. (42 U.S.C. 1395cc.) The
Patient Self-Determination Act requires these facilities to give
information to patients about their rights under State law to accept or
refuse treatment and to make advance directives. These facilities also
are required to document in the patient's medical records whether the
patient has executed an advance directive and to ensure compliance with
State laws on advance directives. The comment did not explain how he
believed the rule violates the Patient Self-Determination Act; nothing
in this rule prevents facilities from continuing to act in compliance
with the requirements contained in that act.
21. Another comment questioned the validity of the claim in the
proposal that ``the proposed rule gives double weight to the statutory
'necessitates' criterion'' because ``(1) intervention is needed because
of the medical condition, and (2) the collection of valid data is
needed

[[Page 51505]]

because of the absence of proven satisfactory available treatment for
the condition.'' This comment stated that the context of the
``necessitates'' clause makes it clear that what is necessary is the
use of a device to preserve the life of the subject--that the
relationship of necessity is between the intervention and the subject's
condition. This comment stated that it is a perversion of the statutory
language to claim that it uses ``necessitates'' to refer to the
relationship between the collection of data and proven treatment. The
comment noted further that randomly assigning subjects to a treatment
that some researchers consider unsatisfactory and to a treatment
researchers think may be an improvement is not necessitated by the
subject's life-threatening condition and, further, a placebo can never
be necessitated to preserve a subject's life.
The agency agrees that the ``necessitates'' clause focuses on the
relationship between the treatment and the subject's condition. The
idea that an intervention using an investigational product is
``necessary'' may, at first, appear to be contradictory. It does not
mean the product is safe and effective and that it must be given to
everyone. Read this way the exception would apply to products that are
not investigational and it would be irrelevant. The device amendments
to the act are referring to an investigational intervention that is not
known to be beneficial, and ``necessitate'' means that because
available therapy is inadequate, potentially beneficial intervention is
needed. Thus, there is no obligation to give everyone the
investigational intervention despite the patient's need for some better
treatment; it is possible to give only some subjects the intervention,
leaving others to the care they would get were there no study. In the
absence of an obligation to give every patient the investigational
intervention, it is possible to consider other factors, such as the
need to evaluate the intervention and learn from the exposure, which
potentially may benefit the subject in the study, the community, and
future patients with the disease. The critical and potentially
difficult concept is that the intervention is given because the
patient/subject needs it, yet enough is not known about the
intervention to support giving it to everyone as therapy.
It is clear, despite the uncertainty, that the investigational
intervention is intended to be beneficial and that there is conceptual,
preclinical, and possibly clinical (e.g., other settings, preliminary
results) evidence that the hoped for benefits outweigh the potential
risks, all of which leads the investigator (and the pertinent IRB) to
hope for, even anticipate, benefit. Such anticipation is compatible
with the state of clinical equipoise needed to allow a clinical
investigation. Indeed, true neutrality is rarely present at the start
of an investigation; in the absence of expectation that an intervention
may represent an improvement, or a belief that a standard therapy might
not work, there is little incentive to proceed. The experienced
clinical investigator, however, also knows that expectations are not
the same as knowledge and that disappointments are too common to
ignore. Therefore, despite optimistic expectations, one can be in the
state of equipoise needed to allow a clinical investigation to be
conducted.
In the current rule, addressing the special case of nonconsenting
subjects, the agency is asking for more than the usual assurances that
the investigational intervention is promising, and that accumulating
results have not taken us all the way past equipoise (through the data
monitoring committee's considerations). This extra assurance is
necessary because it must be possible to state honestly that the
intervention is for the patient's benefit, at least at the level of
being promising, and is not a project only for pure science, future
generations, or the community, although it will, of course, benefit
those too.
Therefore, if there are available only unproven or unsatisfactory
therapies and appropriate animal and other preclinical studies support
the potential of benefit to subjects from a new intervention, the
agency thinks it can be said that the subject's condition
``necessitates'' alternative treatment. In the case under
consideration, where the new intervention is not known to be of value,
although it is promising and has been evaluated in animals and in less
emergent settings, it is reasonable to randomize to a standard therapy
not yet shown inferior to the new intervention. The subject receiving
standard therapy is no worse off than if there had been no clinical
investigation.
22. Another comment considered the rule contrary to the Nuremberg
Code and to the U.S. Constitution; it stated that the agency's reliance
on Doe v. Sullivan is inappropriate. Another comment suggested that the
decisions of the U.S. Supreme Court in Cruzan v. Director Mo.
Department of Health, and Griswald v. State of Connecticut present
constitutional barriers to the proposal to eliminate the requirement of
informed consent in biomedical research involving emergency conditions.
This comment also analyzed an attorney's observations at the Public
Forum with respect to State law and criticized the proposal for not
addressing these. Another comment stated that the rule denies persons
with disabilities equal protection under the law and their rights to
due process in that it treats competent and incompetent patient-
subjects in a distinct, unequal manner.
FDA disagrees with these comments and with the assertions that the
cases cited present constitutional barriers to the issuance of this
rule. FDA strongly endorses the concept of informed consent. Obtaining
informed consent is not always possible, however, as Congress has
recognized in enacting amendments to the Act. Congress explicitly has
authorized exceptions from the requirement for informed consent in
research in limited situations. (See preamble to the proposed rule for
a more detailed discussion of authority in the act for permitted
exceptions from informed consent (60 FR 49086)).
Unlike situations involving a failure to inform a competent person
of the risks and consequences associated with participating in research
(see In Re Cincinnati Radiation Litigation, 874 F. Supp. 796, 800-01
(S.D.Ohio 1995)), this rule seeks to maximize an individual's access to
potentially beneficial drugs and devices at a time when, due to an
emergency which causes incompetency, informed consent cannot be
obtained. The issuance of this rule does not result in the automatic
entry of an individual in a clinical investigation without informed
consent. Rather, it contains important protections that must be met
before such a clinical investigation may proceed. Decisions on whether
an investigation may proceed will be made on a case-by-case basis by
individual IRB's and need the concurrence of a licensed physician.
Contrary to the comment's suggestion, the Supreme Court's decision
in Cruzan v. Director Mo. Department of Health does not create a hurdle
to the issuance of this rule. In Cruzan v. Director Mo. Department of
Health, 497 US 261 (1990), the Supreme Court, in reviewing a Missouri
statute which required clear and convincing evidence of an incompetent
person's wishes as to whether or not life-sustaining treatment should
be employed, balanced a State's interest in the preservation of life
with an individual's wish to terminate life support rather than remain
in a vegetative state. Unlike Cruzan, this rule focuses on the
preservation of life when an individual's wishes are unknown. As in
other emergency situations, where an individual is incompetent, if it
is feasible to obtain informed consent from the individual's legally
authorized

[[Page 51506]]

representative, then such consent should be obtained. FDA notes that it
is possible that an individual may have previously issued advance
directives on life-sustaining treatment. FDA believes that, where
feasible, attempts should be made consistent with State law to identify
the existence of such directives prior to enrolling an individual into
a clinical investigation without informed consent. FDA recognizes,
however, that in many life-threatening instances it may not be feasible
to learn of the existence of any existing directives prior to taking
potentially life-saving intervention and that in many instances, an
individual may not have issued such advance directives. In such cases,
FDA believes that interventions consistent with this rule are
constitutionally permissible.

H. Clarifications

23. HIMA noted that it was one of the organizations that endorsed
the October 25, 1994, consensus document on Informed Consent in
Emergency Research from the Coalition Conference of Acute Resuscitation
and Critical Care Researchers.
The agency acknowledges that HIMA endorsed the consensus document
on Informed Consent in Emergency Research from the Coalition Conference
of Acute Resuscitation and Critical Care Researchers.
24. HIMA also suggested that FDA recognize the diversity of opinion
on ``deferred consent'' and its history of successful use from
approximately 1980 until mid-1993, rather than simply disregard this
concept as ``post-hoc ratification'' unworthy of ``genuine'' informed
consent.
FDA disagrees and thinks that its earlier rejection of ``deferred''
consent was appropriate. As described in the preamble to the proposed
rule, posthoc ratification is not genuine consent because the subject
or representative has no opportunity to prevent the administration of
the test article, and cannot, therefore, meaningfully be said to have
consented to its use.

III. Specific Comments on the Proposed Regulation

A discussion of the specific comments received in response to this
proposal follows:

A. Definitions

25. Four comments requested clarification of the proposed
definition of family members in Sec. 50.3. Two comments questioned what
one should do if there is disagreement among family members. One asked
whether a family member could provide informed consent for emergency
research if State law does not explicitly provide for consent from
family members. Another questioned whether family members, even those
who do not possess power of attorney for health care rights, can
provide informed consent for emergency research under this rule.
One individual suggested that it may be unwise to provide a new
definition for such a familiar expression as ``family member'' and
suggested that the phrase ``any individual related by blood or affinity
whose close association with the subject is the equivalent of a family
relationship'' be used in its place. Another comment commended the
agency for including in its definition those individuals whose
relationship resemble family relationships.
One comment suggested that the hierarchy of the decision-making
authority of family members should be clearly stated. This comment
questioned whether one family member could overrule the decision of
another and questioned whether all family members must agree.
The agency thinks that it is appropriate to retain the phrase
``family member'' and its definition. The agency has specifically
included family members under this rule because the opportunity for an
available family member to object to a potential subject's
participation in such a clinical investigation provides an additional
and an important protection to these individuals. Otherwise, if consent
from a subject or the subject's legally authorized representative were
not feasible, the eligible individual could be enrolled into the
investigation. Thus, by permitting a family member (even one who is not
a legally authorized representative) to object to an individual's
inclusion in the investigation, a further protection is provided to
that individual. This rule has been modified to make clear that a
family member must be provided an opportunity to object to the
potential subject's participation, if feasible within the therapeutic
window when obtaining informed consent from the subject is not feasible
and a legally authorized representative is not available. The agency
recognizes that this may not constitute legally effective informed
consent if the family member is not a legally authorized representative
under State law. FDA is not establishing a hierarchy of family members
although an IRB may consider the need for creating a hierarchy in
reviewing individual investigations. Under this rule only one family
member would need to be consulted and agree or object to the patient's
participation in the research. If family members were to disagree, the
researcher and family members would need to work out the disagreement.
26. One individual, who was opposed to the entire rule, suggested
that by not providing a definition of ``emergency,'' FDA's quest for
harmony and uniformity would be defeated by the various definitions
provided by State law. He suggested that without such a definition, too
much discretion is delegated to medical researchers and IRB's; that the
agency will have little basis to monitor the activities carried out by
these researchers; and that the exception will be used to exempt all
emergency research from consent, even when it is feasible to
prospectively identify and secure the consent of hospitalized
individuals. Finally, he noted that the Health Care Financing
Administration has issued regulations under the Emergency Medical
Treatment and Active Labor Act which define the term ``emergency
medical condition;'' this act's regulations link an emergency medical
condition to the manifestation of ``acute symptoms of sufficient
severity * * * such that the absence of immediate medical attention
could reasonably be expected to result in: (a) Placing the health of
the individual * * * in serious jeopardy; (b) serious impairment to
bodily functions; [or] (c) serious dysfunction of any bodily organ or
part.'' He suggested that health care professionals will be confused by
the different use of the term ``emergency'' in this regulation and
under the Emergency Medical Treatment and Active Labor Act.
The agency disagrees with these comments. Sufficient guidance is
given in the regulation in Sec. 50.24, particularly in
Sec. 50.24(a)(2)(iii), to ensure that there is a clear understanding of
what constitutes a life-threatening situation that could invoke this
rule and to ensure that it is not used routinely in all emergency
research. In addition, each clinical investigation will be reviewed by
FDA and the IRB to help ensure that this exception from informed
consent is not used for research for which it was not intended.
Further, emergency room personnel should not be confused because they
should know when they are participating in FDA regulated research. The
agency notes that the purpose of the Emergency Medical Treatment and
Active Labor Act is different from this rule. This informed consent
exception is intended to allow certain FDA-regulated research to
proceed without informed consent provided specific conditions are met.
Entities that deal with both regulations

[[Page 51507]]

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

B. Exception Criteria

1. Section 50.24(a)
27. One comment suggested that additional conditions be added to
Sec. 50.24(a) to reinforce the statement in the preamble to the
proposed rule that appropriate evidence is available to document
clinical equipoise and to ensure that efforts are made to obtain
consent from a legally authorized representative whenever possible. The
two proposed additional sections would read: ``[a]ppropriate animal and
preclinical trial studies have been completed, and the information
derived from those and related studies support the likelihood of
providing a direct benefit to the individual subjects'' and ``[t]he IRB
finds that the researcher defined the length of the therapeutic window
based on scientific evidence, will try to contact the legally
authorized representative within that window of time, and will ask each
representative contacted for consent within that window rather than
waive consent. The researcher will track the number of representatives
contacted and provide that information to the IRB.''
The agency agrees that these are important concepts that should be
contained explicitly in the regulation. It has incorporated these
comments in the regulation, with slight modification to the language
proposed in the comment. The agency has added a new paragraph to
Sec. 50.24(a)(3) to read as follows: ``(ii) Appropriate animal and
other preclinical studies have been conducted, and the information
derived from those studies and related evidence support the potential
for the intervention to provide a direct benefit to the individual
subjects.'' The agency also has added a new paragraph Sec. 50.24(a)(5)
and a new paragraph Sec. 50.24(a)(7)(v). The new paragraph
Sec. 50.24(a)(5) reads as follows: ``(5) The proposed investigational
plan defines the length of the potential therapeutic window based on
scientific evidence, and the investigator has committed to attempting
to contact a legally authorized representative for each subject within
that window of time and, if feasible, to asking the legally authorized
representative contacted for consent within that window rather than
proceeding without informed consent. The investigator will summarize
efforts made to contact legally authorized representatives and make
this information available to the IRB at the time of continuing
review.'' The new paragraph Sec. 50.24(a)(7)(v) reads as follows: ``(v)
If obtaining informed consent is not feasible and a legally authorized
representative is not reasonably available, the investigator has
committed, if feasible, to attempting to contact within the therapeutic
window the subject's family member who is not a legally authorized
representative, and asking whether he or she objects to the subject's
participation in the clinical investigation. The investigator will
summarize efforts made to contact family members and make this
information available to the IRB at the time of continuing review.''
The agency notes that if the window of time is narrow, it will be
difficult or impossible to identify a legally authorized representative
or family member, especially for potential subjects whose identities
are unknown at the time of presentation.
28. One comment suggested that, in order to prevent abuses, the
agency provide all IRB's with standardized forms that strictly define
the circumstances and process for an IRB to invoke the waiver of
informed consent.
The agency does not think that standardized forms would be useful
or practical. The regulation provides sufficient information and allows
flexibility for each IRB to develop procedures and methods (and forms,
if necessary) to fulfill its requirements.
29. Several wording changes were suggested to clarify
Sec. 50.24(a). Two comments suggested that Sec. 50.24(a) be revised to
add ``prior to initiation of research'' after the words ``without
requiring that informed consent be obtained'' in order to stress that
consent is being waived for the necessary immediate intervention.
The agency thinks this change is unnecessary. This is clear from
Sec. 50.24(a)(2) and new Sec. 50.24(a)(5).
30. One comment suggested the addition ``of all research subjects''
following the phrase ``without requiring that informed consent'' and
modifying the parenthetical phrase in the next sentence to read:
``(with the concurrence of a licensed physician voting member of the
IRB or the concurrence of a licensed physician who serves as a
consultant).''
The agency has incorporated this language, with minor changes, to
emphasize the need for concurrence by a licensed physician who is
either an IRB member or consultant and who is not otherwise
participating in the clinical investigation. The agency recognizes that
in some instances it will be possible to obtain informed consent from
some individuals or their legal representatives, or contact a family
member when this exception is invoked for a clinical investigation. The
agency has not included the term ``voting'' because it does not believe
that it is necessary to explicitly require that this licensed physician
who concurs be a voting member of the IRB because concurrence by this
licensed physician is required by the regulation. Since 1981, FDA has
stated its expectations that an IRB that reviews investigational new
drug studies will include at least one physician. (See 46 FR 8942 at
8966, January 27, 1981.) This expectation is not changed by this rule.
31. Other comments were received on the ``concurring licensed
physician member or consultant.'' Three comments felt that this
physician member or consultant would add nothing to the process because
of pressure to endorse the study; one comment suggested that the
interests of subjects would be better served if this physician or
consultant were independent of the IRB; two comments suggested that the
physician be independent of the investigator (i.e., have no ties to or
be in the same department or supervised by, the investigator).
The requirement for a concurring licensed physician is contained in
the Medical Device Amendments of 1976 and, thus, it must be retained.
The agency agrees with the need for this individual to be independent
from the clinical investigation but disagrees with the suggestion that
the physician be independent of the IRB. Thus, the agency has amended
the language in Sec. 50.24(a) to make clear that the licensed physician
must be one who is not otherwise participating in the clinical
investigation. This language parallels the language contained in
Sec. 50.23(a).
32. One of these comments suggested that an independent ombudsman
who is aware of the acute risks of the specific research, the long term
risks of the research for the individual, family, and society, based on
the condition of the potential subject be appointed to oversee the
study.
The agency does not agree. There is no need for a special
requirement for an ombudsman for these clinical investigations. Current
Sec. 50.25(a)(7) requires the consent form to contain an ``explanation
of whom to contact for answers to pertinent questions about the
research and research subjects' rights, and whom to contact in the
event of a research-related injury to the subject.'' It may be the IRB
or some other designated individual who performs these ombudsman-type
functions for these investigations.

[[Page 51508]]

2. Section 50.24(a)(1)
33. A few comments expressed concern about the phrase contained in
Sec. 50.24(a)(1) that ``available treatments are unproven or
unsatisfactory.'' One comment suggested that ``unproven'' be changed to
``ineffective.''
The agency disagrees with this suggestion because one may have
insufficient data to know whether a treatment is ineffective. One may,
however, know from the limited data available that it is ``unproven.''
34. Another comment suggested that the phrase ``available
treatments are unproven or unsatisfactory'' be changed to read ``the
efficacy of available treatments has not been demonstrated, or is
regarded as unsatisfactory.''
The agency does not believe this change is necessary or desirable.
Available treatments need to be assessed in terms of both safety and
effectiveness. The agency believes that the change proposed in the
comment focuses solely on effectiveness.
35. Another comment expressed concern that nonscientific members of
IRB's will have a particularly difficult time making determinations
about whether available treatments are unproven or unsatisfactory.
The agency disagrees. Current Sec. 56.107(a) requires the IRB
membership to possess the professional competence necessary to review
specific research activities. Further, current Sec. 56.107(f) permits
an IRB to invite ``* * * individuals with competence in special areas
to assist in the review of complex issues which require expertise
beyond or in addition to that available on the IRB.'' Thus, the IRB
should have sufficient information from its own professional expertise,
or from consultants, to make determinations about whether available
treatments are unproven or unsatisfactory.
36. One comment suggested that guidance on the criteria for
determining that current therapy is unsatisfactory should be provided
or that the rule should explicitly recognize that IRB's have the
discretion to make independent decisions on this point. One comment
suggested that a study be allowed to proceed if there is an alternative
therapy, provided that equipoise exists between the investigational
product and current therapy.
It is clear from the existing wording in Sec. 50.24(a) that it is
the IRB's responsibility to make decisions as to whether the criteria
in the rule are met. The agency notes that it will also be reviewing
these clinical investigations and will evaluate whether these
investigations meet the criteria in this regulation. There is nothing
in this rule that would prohibit an investigation from proceeding if
there is an alternative therapy where the alternative therapy is
unproven or unsatisfactory. The agency expects that in most clinical
investigations under this rule, the experimental intervention will be
added to standard therapy. That is, subjects in the investigation would
receive standard therapy, with a portion of the subjects receiving the
investigational product in addition. In some clinical investigations,
some subjects may receive standard therapy, while others may receive
the investigational product instead of standard therapy because, for
example, use of the investigational product precludes use of the
standard treatment. In these latter investigations, the IRB may need to
look more closely at why standard therapy is unproven or
unsatisfactory, and may want to review additional preclinical data or
results in less ill human subjects that the intervention is promising,
because the standard care will not be provided to a portion of the
subject population.
37. Other comments suggested that without clear definitions for
``unsatisfactory'' and other terms used in the proposal's preamble to
describe clinical equipoise, i.e., `unknown,'' ``believe,'' and
``reasonable minority,'' that abuse of the consent exception is likely.
The agency disagrees with these comments. The agency has explained
this provision in more detail in the preamble to the proposed rule and
believes that such definitions are unnecessary. The agency also notes
that the conduct of this research will be carefully monitored and will
be subjected to public scrutiny through the requirements for community
consultation and community disclosure. In the preamble to the proposed
rule, the agency stated that ``[w]hen the relative benefits and risks
of the proposed intervention, as compared to standard therapy, are
unknown, or thought to be equivalent or better, there is clinical
equipoise between the historic intervention and the proposed test
intervention. Clinical equipoise would exist * * * whenever at least a
reasonable minority of medical professionals believe the experimental
treatment would be as good as, or better than, the standard
treatment.'' (60 FR 49086 at 49093, September 21, 1995.) The agency
thinks that this description provides sufficient guidance to IRB's and
that it is appropriate to allow IRB's to determine when clinical
equipoise exists.
38. A number of comments suggested that the scope of the research
covered by the proposed rule and contained in Sec. 50.24(a)(1) be
extended to conditions beyond those that are immediately life-
threatening so that conditions that result in permanent disabilities,
such as a long-term or permanent coma, or conditions that would result
in other serious irreversible injury are included under the rule. One
example given was a near-drowning patient resuscitated in the
prehospital setting who arrives at the Emergency Department comatose;
the acute injury may no longer be immediately life-threatening, but the
chances that the patient will regain consciousness again are highly
unlikely. One comment noted that FDA has in the past interpreted
``life-threatening'' to include threats of serious disability and, if
this is intended in the proposed rule, it would be helpful to add this
interpretation to the supplementary information. Another comment
suggested that both stroke and head injury do not necessarily
immediately result in death and that potentially effective treatments
are being developed for these conditions which may leave the patient
with profound deficits. This comment proposed that such emergencies be
covered under the final rule. Two comments suggested that ``life-
threatening'' be defined and limited to include only those situations
believed to be immediately life-threatening. Another comment suggested
that ``emergency privilege'' is limited and should extend to care
needed to stabilize or prevent further deterioration of the patient's
condition as well as care necessary to prevent death or serious bodily
injury or harm. Therefore, the care justified must be balanced with the
emergent nature of the patient's condition, the patient's potentially
transient incompetence to make decisions and give consent, and the time
needed to make a reasonable effort to contact and involve the patient's
family.
The agency notes that the Medical Device Amendments limit this
exception to life-threatening situations; the agency and the IRB will
need to judge each clinical investigation to ensure that it meets the
criteria of the statute and regulations. Specifically, the IRB must
conclude that the intervention to treat a life-threatening condition
must be administered before consent can be obtained.
The criteria contained in the rule do not require the condition to
be immediately life-threatening or to immediately result in death.
Rather, the subjects must be in a life-threatening situation requiring
intervention before

[[Page 51509]]

consent from a legally authorized representative is feasible. Life-
threatening includes diseases or conditions where the likelihood of
death is high unless the course of the disease or condition is
interrupted. (See Sec. 312.81.) People with the conditions cited in the
examples provided in the comments--e.g., long-term or permanent coma,
stroke and head injury--may survive for long periods but the likelihood
of survival is not known during the therapeutic window of treatment.
People with these conditions are clearly at increased risk of death due
to infection, pulmonary embolism, progression of disease, etc. The rule
would apply in such situations if the intervention must be given before
consent is feasible in order to be successful. The informed consent
waiver provision is not intended to apply to persons who are not in an
emergent situation, e.g., individuals who have been in a coma for a
long period of time and for whom the research intervention should await
the availability of a legally authorized representative of the subject.
39. The agency received a number of comments on the reference to
placebo-controlled trials in Sec. 50.24(a)(1). One comment stated that
it was vitally important to retain the reference. Other comments
requested that the reference be removed. Reasons given for its removal
included concern that placebo-controlled studies will not meet the
requirement of clinical equipoise unless the placebo control is the
standard of care for the situation or there is absolutely no standard
therapy; that this conflicts with agency statements that the use of a
placebo is not necessary when the end-point is clear and reasonably
predictable; it is inappropriate for the agency to specify one study-
design among many; and that unless the potential subject or legally
authorized representative can consent, a placebo should not be an
alternative.
Some of the comments appear to presume that in a placebo-controlled
trial, the placebo group would be untreated. In virtually all cases,
when a placebo is used, standard care, if any, would be given to all
subjects, with subjects randomized to receive, in addition, the test
treatment or a placebo. An exception to this would be the situation in
which the test is to determine whether standard treatment is in fact
useful. In that case, there must be a group that does not receive it.
The agency believes that it is important to recognize in the regulation
that placebo-controlled trials may be conducted under this emergency
research provision; thus, it is retaining the wording in this section.
Different kinds of controls are described in FDA's regulations. For
example, FDA regulations for drugs (Sec. 314.126) describe five kinds
of study designs that can be used in carrying out the well-controlled
investigations needed under law to provide the ``substantial evidence
of effectiveness'' needed to market a drug. They are: Placebo
concurrent control, dose-response concurrent control, no-treatment
concurrent control, active treatment concurrent control, and historical
control. In any given year, drug approvals will be based on clinical
investigations using each of these designs. The study design used must,
however, be adequate to the task of providing evidence that the drug or
device will have the effect claimed.
40. Two comments suggested changing the wording of Sec. 50.24(a)(1)
from ``what particular intervention is most beneficial'' to ``the
safety and efficacy of a particular intervention'' in order to provide
greater flexibility. Another comment suggested that ``most beneficial''
be followed by the clarifying phrase ``to patients in the life-
threatening situation.''
The agency agrees that it would be more precise to indicate that
the clinical investigation is necessary to determine whether a
particular intervention is safe and effective and it has modified the
wording in the regulation accordingly.
3. Section 50.24(a)(2)
41. A number of comments on Sec. 50.24(a)(2)(ii) recommended that
``or family members'' be added to ``legally authorized
representatives'' at each occurrence in the proposal and in its
conforming amendments in order to ensure that the exception is used
only in those cases where it is not feasible to contact the legally
authorized representative or a family member.
The agency generally agrees with these comments for the reasons
previously stated and has modified the regulations accordingly.
42. Two comments requested that a definition of the term ``legally
authorized representative'' be provided. One comment suggested that the
language be clarified to read ``* * * consent from the subjects'
legally authorized representatives is feasible.''
``Legally authorized representative'' is currently defined in
Sec. 50.3(m) to mean ``an individual or judicial or other body
authorized under applicable law to consent on behalf of a prospective
subject to the subject's participation in the procedure(s) involved in
the research.'' This definition is being retained in the regulation.
The agency has added the clarifying language that it is ``the
subject's'' legally authorized representative.
43. One comment questioned whether one should seek oral consent/
assent from a family member or other individual in those instances in
which there may only be a few moments to convey the nature of the
intervention, precluding full informed consent. If such assent is not
given, the comment requested clarification on options available to the
researcher.
If it is feasible to obtain informed consent for some potential
subjects, informed consent is required for those individuals. If there
is insufficient time to obtain informed consent for some potential
subjects, but there is sufficient time to convey some basic risk and
benefit information about the clinical investigation, then that
information should be provided to the subject, the subject's legally
authorized representative, or the subject's family member. If the
subject, legally authorized representative, or family member objects to
the individual's inclusion in the investigation based upon the
information provided, then that individual should be excluded from
participation in the clinical investigation. If only partial
information was conveyed, then the information described in
Sec. 50.24(b) is to be provided at the earliest feasible opportunity.
44. Another comment suggested that there be a requirement that the
determination that a subject cannot provide informed consent and
efforts made to obtain informed consent from the subject's legally
authorized representative be documented and notarized by an individual
not directly involved in the research. This comment suggested that
without such a requirement, investigators are likely to make little
effort to obtain consent from subjects prior to enrollment. This
concern was echoed by another comment, which suggested that the
investigators' documentation of efforts to obtain informed consent
would encourage researchers to expend greater efforts to obtain
informed consent for these activities. Another comment suggested that
this documentation be made by an individual not affiliated with the
study team.
The agency expects the IRB to determine, based on the specific
details of the individual clinical investigation (including the window
of opportunity for treatment), the procedures the investigator must
follow to attempt to obtain informed consent before enrolling a subject
in an investigation without such consent. The agency has added a new
paragraph Sec. 50.24(a)(5) that requires the investigator to attempt to

[[Page 51510]]

contact a legally authorized representative for each subject within the
therapeutic window and, if feasible, ask for consent within that window
rather than proceeding without consent. The agency also has added a new
paragraph Sec. 50.24(a)(7)(v) that requires the investigator to attempt
to contact a family member within the therapeutic window and ask
whether the family member objects to the subject's participation in the
clinical investigation, if informed consent is not feasible and a
legally authorized representative is not available. IRB's may create a
hierarchy of family members or impose other conditions to increase the
protections provided to research subjects. These paragraphs further
require the investigator to summarize efforts made to contact
representatives and family members and to make this information
available to the IRB at the time of continuing review. The agency
believes that these procedures will ensure that appropriate efforts are
made by the investigator to obtain consent from subjects prior to
enrollment. The agency expects these procedures to be documented in the
protocol and/or by the IRB, and the efforts made by investigators to be
documented in the material presented to the IRB for its continuing
review. The agency believes that this documentation provides the
necessary protections suggested by these comments.
45. One comment suggested that Sec. 50.24(a)(2)(iii) be modified to
read ``There is no reasonable way to identify prospectively the
individuals likely to become eligible for participation in the research
study,'' omitting the remainder of the sentence.
The agency agrees that the last phrase in the proposal that read
``because the emergence of the condition to be studied cannot be
predicted reliably in particular individuals'' is not needed and it has
therefore deleted this phrase from the final rule as suggested.
46. Although two comments stressed the importance of retaining the
word ``reasonable'' in order to allow IRB's to exercise the judgment
necessary to make satisfactory decisions about application of the
exception in particular contexts, another comment suggested that the
term ``reasonable'' may provide more flexibility than is desirable.
The agency thinks that IRB's must be allowed to make responsible
judgments when they review clinical investigations, and that it is
important to retain the term ``reasonable'' in order to permit the IRB
to judge the particular circumstances surrounding each investigation
under review.
47. One comment asked how to document the case where prospective
individuals have been notified and prior consent for participation has
been sought in an institution with several co-investigators or where
more than one institution in the area may be participating in the
research. The comment asked further whether only those subjects with
the condition who gave prior consent could be enrolled and whether
those who did not render a decision would be excluded from
participation in the study.
Generally, the agency recommends that when prospective consent is
being sought in an institution, the documentation that a potential
subject consented or refused to consent be placed prominently in the
subject's medical file. Consent will typically be documented through a
signature on the consent form. It is the responsibility of the clinical
investigator to determine how to identify prospective subjects who have
agreed or refused to participate in a clinical investigation if they
should become eligible in order to help ensure that their decisions are
followed. When an IRB determines that it is not appropriate to waive
the requirement of informed consent because there is a reasonable way
to identify prospectively the individuals likely to become eligible for
the clinical investigation, then only those subjects with the condition
who gave prior consent may be enrolled in the investigation. Those
individuals who either did not make a decision or who refused would be
excluded from participation in the investigation.
48. Another comment noted that if a subset of the general
population can be identified as potential subjects, anticipatory
informed consent must be obtained, even if the subset is a very small
percentage of a large patient population. For example, where a small
percentage of patients undergoing a standard procedure may suffer a
complication that would render them unconscious and make them potential
subjects, informed consent should be obtained for that clinical
investigation. The comment went on to note that if that procedure
carries some known risk for a complication, the potential subjects
would need to be informed of that risk in any event, and obtaining
anticipatory consent for the investigation should therefore not be
burdensome.
The agency generally agrees with the concept that obtaining
anticipatory consent from a target population where the complication
rate is modest often would be feasible. As the complication rate grows
small and the population hard to identify, this strategy becomes
problematic. Each clinical investigation must be judged individually by
FDA and the IRB.
49. Another comment suggested that the Coalition Conference
Consensus Statement wrongly discounted the value of securing and the
ability to secure prospective consent from identifiable individuals at
high risk for study enrollment, particularly those in hospitals, and
that neither the consensus statement nor the proposed rule mentioned
the role of advance medical directives in guiding enrollment decisions.
This comment, supported by others, suggested that a good faith effort
should be mandated to locate advance directives and that the regulation
should include a new paragraph, as follows: ``Any individual likely to
be eligible for a research protocol under this section may not be
enrolled in the research if the investigators know, or reasonably
should know, that the individual did not want to receive medical
interventions of the type under study.'' Another comment suggested
that, although advance directives have been addressed in clinical
practice, their application to the conduct of clinical research has not
received much scrutiny. This comment described the difficult task for
potential subjects to imagine the kind of research they would want
should they suffer a catastrophic illness; it went on to recommend that
either FDA clarify how it intends clinical investigators to adopt the
practice of advance consent, or this statement should be deleted. It
further suggested that FDA consider requiring the use of consent
auditors whose role would be to determine whether the subject truly
understands the consent process.
The agency does not believe that these comments require a change in
this regulation. The agency recognizes that it may be possible in some
situations to secure prospective consent from identifiable individuals
at high risk for study enrollment, particularly if they are inpatients.
It is for that reason that the agency has included
Sec. 50.24(a)(2)(iii), which requires the IRB to determine that there
is no reasonable way to identify prospectively the individuals likely
to become eligible for the clinical investigation. Both the American
Hospital Association's Patient Bill of Rights and section 4206 of the
Omnibus Budget Reconciliation Act of 1990 recognize a patient's right
to participate in and direct health care decisions affecting the
patient. The agency agrees, particularly for clinical investigations
involving inpatients, that

[[Page 51511]]

appropriate efforts be made to review the patient's medical file to
determine whether there exists an advance medical directive or other
indication of the patient's desires (e.g., do not resuscitate order).
However, the agency also recognizes that, for at least some of the
research that will be eligible for this exemption, there will be
insufficient time to search for or locate such directives. The IRB
should be knowledgeable about an institution's procedures regarding the
use of advance medical directives and assess whether the proposed
clinical investigation is consistent with those procedures.
As discussed previously, if an IRB determines that it is not
appropriate to waive the requirement of informed consent because there
is a reasonable way to identify prospectively the individuals likely to
become eligible for the clinical investigation, then only those
subjects with the condition who gave prior consent may be enrolled in
the investigation. Those individuals who either did not make a decision
or who refused would be excluded from participation in the
investigation. For research where individuals can give informed consent
prospectively, the individual's consent or refusal should be documented
in such a way to ensure that the individual's determinations are
followed. As in other research that is reviewed by an IRB, it is up to
the IRB to determine whether there is a need for a consent auditor.
50. Another comment recommended that the question of whether prior
consent of subjects must be obtained should be resolved by considering
the following questions: (1) From which populations will subjects be
drawn; (2) what is the probability that any particular member of the
at-risk population will become a potential subject; (3) where is the
population from which subjects will be drawn; (4) how much effort is
needed to inform the population of the study; and (5) what is the most
effective communications media or mechanism to reach the population.
Based on these questions, this comment recommended that a new section
be added that would state: ``When individuals likely to become eligible
for the research are members of identifiable and accessible populations
of the community at large, reasonable effort to target communications
to those sub-populations should be made.''
This comment suggests what may be a reasonable thought process for
an IRB to follow. However, it combines two different concepts:
communication with the community and prior consent of individual
subjects. As the agency has previously stated, if one can obtain prior
consent of subjects, that should be done. Examples of situations where
it may be feasible to obtain prior informed consent include: use of a
surgical procedure with a known severe consequence; administration of a
drug product with a known serious adverse reaction; identification of a
population with a particular disease or condition who are at an
extremely high risk for a serious event. In each of these instances, it
may be feasible to identify in advance the specific patient population
susceptible to the condition being studied and obtain consent. The
agency believes that it would be inappropriate to add the suggested
section to the regulation because it confuses efforts to inform the
community with efforts to obtain prior consent of the individual.
51. Another comment recommended that the agency require preliminary
studies of new products in patients admitted to intensive or critical
care units who are able to consent or who have a legal representative
who can consent on their behalf. This comment suggested that this would
strengthen an inadequacy in the existing regulations that permits
studies (with subjects unable to provide informed consent) to begin,
without any knowledge regarding the clinical performance of the drug/
device.
Given the nature of the product and the medical condition, this
suggestion may not be feasible for many of these clinical
investigations. The agency, in its review of these investigations, will
review the adequacy of the information about the proposed intervention
to help ensure that there is sufficient knowledge, including clinical
performance in other settings when possible, of the drug or device to
justify its use in such investigations. In addition, the regulation has
been modified to specify that evidence from appropriate animal and
other preclinical studies support the potential for the intervention to
provide a direct benefit to the individual subjects.
4. Section 50.24(a)(3)
52. A number of comments suggested deleting the phrase ``is in the
interests of the subjects'' in Sec. 50.24(a)(3) in part because this
phrase requires that a judgment be made about subjects whose interests
may be largely, if not totally, unknown to the IRB and to the
investigators. Some comments argued that there would be no possible
benefit to the subject, but only to society at large if the
experimental intervention were shown to be effective; the goal of the
research is not to benefit subjects in the research, but rather to
benefit science in the pursuit of knowledge. Others suggested that
Sec. 50.24(a)(3) be modified to read: ``The opportunity to participate
in the research holds out the prospect of direct benefit to the
subjects because * * *.'' Other comments objected to the word
``opportunity'' as being disingenuous and paternalistic and suggested
that this section be modified to read: ``Participation in the research
* * *.''
The agency agrees that Sec. 50.24(a)(3) should be modified in
response to some of these comments. The first comment points out that
one cannot really know about all the interests of a person in these
situations. The modification would make clear that the clinical
investigation holds out the prospect of direct benefit to the subjects.
The agency does not agree with the second comment that there would be
no possible benefit to the subject, but only to society at large. To
justify the use of this exception the IRB must believe that
participation in the study holds out the prospect of direct benefit to
the subjects. It is also true, but not the basis for the exception,
that the interests of society will be served by the waiver because the
research will produce valuable knowledge, applicable to future
patients, that would otherwise never be obtained; an IRB should not
approve a clinical investigation that is poorly designed and, thus,
unable to answer the scientific question posed. In response to the
third suggestion, the agency is clarifying any mis-impression that it
would be the ``opportunity'' rather than the actual ``participation''
in the research that is beneficial. The agency intended that
participation in the research should hold out the prospect of direct
benefit to the subject and has revised the rule accordingly.
53. Another comment noted that if the null hypothesis is plausible,
that is, if the effect of the investigational intervention is no
different from that of the standard treatment, the subject has little
to gain by being in a randomized trial rather than being treated by
whichever arm of the study is standard. This comment recommended that
historical controls be used when investigators or potential subjects
are not ``indifferent'' to the treatment alternatives.
If the use of a historical control is appropriate for the clinical
situation being studied, that control may be used, but the difficulties
of this design are well-known and it cannot reliably assess small, but
potentially meaningful benefits and is frequently associated with false
positive results. The comment related to the null hypothesis is not
unique to emergency research. Rather, it reflects a fundamental ethical
dilemma

[[Page 51512]]

in all clinical trials. This dilemma, however, has not been considered
by most bioethicists as an impassable obstacle for the conduct of
controlled trials. This is because continuing an intervention, even one
thought to have promise, without determining that it does provide
benefit, is not a responsible alternative. The investigational
intervention in these clinical investigations must be promising, but
one does not know that it is in fact safe and effective. Further, in
these investigations, the standard treatment being compared to the
investigational product or to which the investigational product is
added will be of unproven benefit or unsatisfactory.
54. One comment suggested that an additional condition be added to
50.24(a)(3) which would require that the weight of scientific evidence
be sufficient to support the likelihood that the individual subjects
will receive a direct benefit. Another comment suggested that the rule
require a progression of research from less severe medical cases to
more severe and only permit the inclusion of patients unable to consent
if there is an ombudsman independent from the research activity.
As previously described, FDA has added a new Sec. 50.24(a)(3)(ii)
which requires that ``Appropriate animal and other preclinical studies
have been conducted, and the information derived from those studies and
related evidence support the potential for the intervention to provide
a direct benefit to the individual subjects.'' There is nothing in this
rule that would preclude research from being conducted in subjects with
less severe medical conditions (not in a life-threatening situation)
before being conducted in subjects with more severe medical conditions
provided that informed consent is obtained from the research subjects
with the less severe conditions. When this exception is invoked for a
particular clinical investigation, however, the FDA, sponsor, clinical
investigator, and IRB will be responsible for ensuring that the subject
population is appropriate; that is, that the subjects are in a life-
threatening situation.
55. One comment recommended that Sec. 50.24(a)(3)(i) be reworded to
clarify that ``subjects are facing a life-threatening situation that
necessitates intervention.''
The agency agrees with the comment and has modified this section
accordingly.
56. One comment suggested that proposed Sec. 50.24(a)(3)(ii) be
reworded to clarify that the rule is addressing the ``prospective
subjects' condition'' and that ``current therapy'' equates to
``standard therapy.'' This comment suggested that proposed
Sec. 50.24(a)(3)(ii) be rewritten to state ``risks associated with the
intervention are reasonable in the light of what is known of the
prospective subjects' medical condition, the risks and benefits of
standard therapy * * *.''
The agency has renumbered proposed Sec. 50.24(a)(3)(ii) to be
Sec. 50.24(a)(3)(iii) in the final rule. The agency agrees with the
comment and has modified this section accordingly. The risk and benefit
assessment that is required by Sec. 50.24(a)(3)(iii) will be conducted
for future subjects meeting the entry criteria for the clinical
investigation; therefore, it is appropriate to refer to these subjects
as the ``potential class of subjects.'' The agency intended that the
risks and benefits of ``standard'' therapy be considered; it recognizes
that ``current'' therapy may be too broad.
57. Several comments requested a definition of ``reasonable.'' One
comment noted that the rule requires a complex judgment about risks and
benefits and yet lacks specificity as to how this judgment is to be
made. This comment noted that in most research, an IRB can rely on the
risks and benefits being explained to the subject and the subject
judging whether they are reasonable. In the case of the research
covered by this regulation, that recourse is not available.
It is not possible to be specific about how to make the judgment
about risks and benefits because, as the comment notes, the judgment to
be made is complex, with different information and considerations
determined by the particular clinical investigation. The agency thinks
that sufficient clarity is contained in Sec. 50.24(a)(3)(iii) to allow
an IRB to understand that it must consider: (1) What is known about the
medical condition, (2) what is known about standard therapy, and (3)
what is known about the proposed intervention or activity. The risks of
the investigation must be considered reasonable in relationship to all
of this information. The agency does not think that this requirement
needs further explanation.
58. Two comments suggested that proposed Sec. 50.24(a)(3)(ii) be
modified to incorporate the Coalition of Acute Resuscitation and
Critical Care Researcher's concept of ``appropriate incremental risk''
stating that this would better protect the rights of subjects. One of
these comments suggested that the 1981 FDA regulatory requirement that
``there is available no alternative method of approved or generally
recognized therapy that provides an equal or greater likelihood of
saving the life of the subject'' is the standard that should be used in
this regulation.
The agency disagrees with both suggestions. The protections
provided by the rule are substantial and sufficient without these
changes. The standard for risks, described in the regulation, are that
they be ``reasonable'' in relationship to what is known of the medical
condition of the potential class of subjects, the risks and benefits of
standard therapy, if any; and what is known about the risks and
benefits of the proposed intervention. The term ``appropriate
incremental risk'' does not have a clearly different meaning, although
it may imply greater precision than usually exists. In order to invoke
this exception, the available treatments must be unproven or be
regarded as unsatisfactory.
5. Section 50.24(a)(4)
59. Several comments suggested deleting or clarifying
Sec. 50.24(a)(4) concerning the ``practicability'' of conducting the
research without the waiver. One comment requested clarification as to
whether ``practicability'' only referred to whether there is sufficient
time to obtain consent from a subject's legally authorized
representative; and recommended that if this is the sole basis for
determining practicability, it should be added to the regulation.
Another comment noted that ``practicability'' should not refer to
convenience, cost, or speed. One other individual commented that
although certain institutions may be unable to perform specific acute
injury research because of logistical considerations, it is likely that
most research projects could be designed such that performance under
existing rules for nonconsenting subjects would be possible in other
locations. This comment cited a multicenter trial where only one
institution requested a waiver.
One comment suggested that Sec. 50.24(a)(2)(ii) is sufficient for
determining whether a study can be done; this comment stated that the
primary reason that it would not be practical to carry out the research
without the waiver would be because it is not feasible to contact the
legally authorized representative or family member before the
intervention must be administered.
Another comment objected to Sec. 50.24(a)(4) and argued that the
rule should state that if there are any potential subjects otherwise
eligible for a trial for whom consent from a legally authorized
representative cannot be obtained, the provisions of Sec. 50.24(a) may
be utilized to include them, even if the trial could be carried out
without

[[Page 51513]]

their participation, so long as all of the requirements for that
section are met. This comment noted that if this section meant only
that consent should be obtained wherever it can be, even when most
subjects in a study do not have an available legally authorized
representative, it would be unexceptionable, but the section goes
beyond that to proscribe participation in a trial by patients without
consent when the majority of eligible patients do have such consent
available because in that case the study can be carried out
``practicably'' without those patients. This comment noted that it is
the value of participation to the subject that permits an exception to
the informed consent requirement; that implicit in the proposal is the
view that most patients would choose a chance to receive promising
rather than standard therapy that is known to have an often
unsatisfactory outcome. Thus, to exclude patients unable to consent
from this research is unethical, even if the study could be conducted
with subjects for whom surrogate consent is possible.
The agency has carefully considered these comments, particularly
the latter comment that in effect contended that the ``practicably''
requirement is inconsistent with the ethical basis for the rule because
it implies that the exception to consent is available to serve the
community's needs rather than the individual's. The agency included
this requirement not because it thought the research was not in
individual patients' interests, but because research without informed
consent represents a more difficult and complex situation than research
with consent, in that it is a kind of research with greater than usual
ethical issues that should be taken only when necessary. This is
because the agency believes it is generally preferable to obtain case-
by-case consent even from a representative of the individual. Just as
consent by the subject is preferable to consent by their
representative, consent by the subject's representative is preferable
to the procedure in this regulation. This does not mean that these
procedures are inadequate or unethical; rather, it recognizes within
the realm of ethically proper actions a hierarchy of values and that we
should seek the highest level of those values feasible in this
situation.
Similar considerations have arisen in the past. The National
Commission for the Protection of Research Subjects of Biomedical and
Behavioral Research argued that (wherever possible) clinical trials
intended to benefit young children should first involve adult subjects,
later older children as subjects, and finally trials in younger
children (who cannot consent or assent). This is not because the trials
in younger subjects are considered inappropriate or ethically doubtful.
The agency understands the Commission to be saying that the principle
of respect for persons of diminished autonomy applies in such a way
that the less autonomy a subject possesses, the less suitable that
subject is for research, even if the research shows promise. The
Commission did not say to never involve persons with minimal or no
capacity to exercise autonomy, but to do so only as a last resort.
It is critical to recognize that an investigation of a promising
(but unproven) intervention is not carried out universally, i.e.,
studies are conducted in particular places. Similarly, although a
parent of a young child could argue that his or her child should not
have to wait for the trial in adults and older children to be completed
before having an opportunity to participate in research, the Commission
was not persuaded by that argument (although, in some cases, early
trials in young children might be carried out). The Commission did not
recognize the right of a needy person to gain access to a research
protocol. In choosing among sites for a clinical investigation, for
example, it is usual to select those in which the skills of
investigators and availability of subjects appear to predict an ability
to carry out the investigation successfully. Similarly, it is
reasonable to consider, in deciding where or in whom to conduct an
investigation, the ability of subjects to consent (or have consent
given for them). Widely accepted ethical principles indicate that a
decision to participate or not to participate in an investigation
should, if at all possible, be made by a competent subject who should
(as stated in the Nuremberg Code) be free of all force, fraud, fear, or
coercion. An exception from the requirement for informed consent should
be rare and narrow, confined to cases where consenting subjects are not
reasonably available. In addition, participation in the research must
hold out the prospect of direct benefit to the subjects and the
investigation must be one that is capable of providing useful
scientific/medical information.
If serving the interests of the subjects were considered sufficient
alone, that would imply that potential subjects have a right to
participate in the trial, an inappropriate consideration for an
investigational use and unrealistic, because studies cannot in fact be
carried out at all potential sites and in all patients.
The agency thus agrees with the comment that it is necessary for
there to be value to the subject from participating in the research;
but, given the general principle of obtaining informed consent where
possible, does not think that such potential benefit is sufficient
justification to include nonconsenting patients when it is reasonably
possible to conduct the clinical investigation in subjects who can
consent.
Therefore, if scientifically sound research can be practicably
carried out using only consenting subjects (directly, or in most cases
for the research contemplated in the rule, with legally authorized
representatives), then the agency thinks it should be carried out
without involving nonconsenting subjects. By practicable, the agency
means, for example, (1) That recruitment of consenting subjects does
not bias the science and the science is no less rigorous as a result of
restricting it to consenting subjects; or (2) that the research is not
unduly delayed by restricting it to consenting subjects.
6. Section 50.24(a)(5)(i)-(a)(5)(iii)--Community Consultation and
Public Disclosure
The greatest number of comments were received on
Sec. 50.24(a)(5)(i) through (a)(5)(iii), which have been renumbered
Sec. 50.24(a)(7)(i) through (a)(7)(iii) in this final rule in order to
have a more logical presentation of information. To assist readers,
these sections will be referred to as Sec. 50.24(a)(7)(i) through (iii)
in the discussion that follows. While most comments supported the
requirement for community consultation and public disclosure, many
requested clarification, offered suggestions, or concluded that
fulfilling these requirements would be impossible. Other comments
questioned whose responsibility it would be to disclose--the clinical
investigator, sponsor, or IRB. These comments are discussed in more
detail below.
60. A number of comments suggested alternatives to the requirement
for Sec. 50.24(a)(7)(i) for consultation with representatives of the
communities from which the subjects will be drawn. These included
limiting this provision to only those diseases for which a patient
advocacy organization exists; relying on the existing IRB mechanism
that already requires inclusion of an individual not otherwise
affiliated with the institution; requiring that IRB's have a community
member or an ad hoc community consultant who is intimately involved
with the projected research population; permitting an IRB to determine
that balanced community consultation is not feasible and documenting
and reporting

[[Page 51514]]

this determination to the sponsor and to FDA; increasing public
participation in the IRB process by specifying acceptable kinds of
individuals (e.g., clergy, local commissioners, police, paramedics) who
should be added to the IRB (limited to two); having the IRB membership
include individuals from the community groups from which subjects would
come and ensuring that the preferences of those members were followed;
establishing a standing community advisory board that would reflect the
diverse values and beliefs of the community. This board could serve
several IRB's within the same community. Another comment stressed that
the IRB must take into account the diverse religious and community
beliefs and attitudes about treatment of the dying and of research.
None of the suggested alternatives to Sec. 50.24(a)(7)(i) would by
themselves provide the protections of broad community consultation of
this section. While an IRB may appropriately decide to supplement its
members with consultants from the community, broader consultation with
the community is needed for this type of research. The agency expects
the IRB to provide an opportunity for the community from which research
subjects may be drawn to understand the proposed clinical investigation
and its risks and benefits and to discuss the investigation. The IRB
should consider this community discussion in reviewing the
investigation. Based on this community consultation, the IRB may
decide, among other things, that it is appropriate to attempt to
exclude certain groups from participation in the investigation; or that
wider community consultation and discussion is needed. As described in
the preamble to the proposed rule (60 FR 49086, September 21, 1995),
IRB's should consider, for example, having a public meeting in the
community to discuss the protocol; establishing a separate panel of
members of the community from which the subjects will be drawn;
including consultants to the IRB from the community from which the
subjects will be drawn; enhancing the membership of the IRB by adding
members who are not affiliated with the institution and are
representative of the community; or developing other mechanisms to
ensure community involvement and input into the IRB's decisionmaking
process. It is likely that multiple methods may be needed in order to
provide the supplemental information that the IRB will need from the
community to review this research.
61. Another comment noted that tribal approval and not just
consultation should be required and suggested that for American Indian/
Alaska Native tribal governments, the regulation require approval by
the tribal government for all research done within its jurisdiction.
This comment suggested that the regulation permit a recognized
government of the political community to disapprove research.
This regulation does not restrict or have an impact on any existing
authority of tribal governments to review and approve or disapprove
research that would otherwise be conducted on persons residing in
tribal jurisdictional boundaries. If existing tribal authorities
require tribal government approval of such research before it proceeds,
then the tribal governments continue to have that authority. Thus, the
agency thinks that adopting this suggestion is unnecessary.
62. Comments opposed to the community consultation required in
Sec. 50.24(a)(7)(i) suggested that the current requirement for a
community representative on the IRB (56.107(a)) was adequate; that this
would be burdensome for noncommercially sponsored studies; that it was
an insurmountable goal and that there is no guarantee that an IRB could
reach all impacted individuals. Other comments suggested that only a
central agency such as FDA or the Public Health Service should decide
because the clinical investigator will bias the outreach meetings to a
disinterested community that would be unable to make knowledgeable
decisions, and the community will be biased because the research would
bring funding support to the community, and because it is difficult to
define the community, especially for those institutions that receive
patients from a large region or State. A number of comments suggested
that community consultation could lead to IRB liability on the basis of
failure to solicit adequate community participation in the decision
process. Other comments noted that disclosure to the community does not
substitute for consent and that unless one included information about
the subject's right to refuse and how to exercise that right, community
consultation would be inadequate.
As discussed previously, the agency does not think that the current
IRB membership requirements adequately substitute for the community
consultation called for in this rule. The agency thinks that community
consultation provides a very important protection for research subjects
and, therefore, every effort should be made by the IRB to involve, and
consult with, the community from which research subjects may be drawn.
63. Other comments stated that without clear definition of terms,
the vagueness of the requirement would lead to inadequate consultation
and disclosure. Another comment noted that if minority or lower income
populations were unlikely to agree to the research and they represented
a large proportion of the potential research population, then the
conduct of the research would violate the principle of justice because
these populations would not share in its benefits or burdens.
The agency thinks that IRB's will ensure, through their review and
oversight activities, adequate consultation and disclosure. It is
impossible, without conscription, to ensure that each subpopulation
shares both the benefits or burdens of all research. Achieving the
principle of justice is a goal that must be balanced by other
principles. In the case of a population that is unwilling to agree to
participation in a research activity, honoring this population's
unwillingness is, in effect, permitting the community to express its
views.
64. A number of comments requested clarification of this
requirement. These comments asked how the consultation should take
place (newspaper, institutional newsletter, advertisement, local radio
stations, meeting); who in the community needs to be informed and who
may be legitimate representatives of the community; what the IRB does
with the community response (e.g., can a community veto research, what
if a small or a large number oppose the research, what is the sponsor
or IRB's responsibility to respond to questions or requested changes in
the research); how is an IRB to assess the effectiveness of the
consultation (e.g., if there is a poor turnout at an adequately
publicized meeting, is the IRB obliged to do more)? Another comment
requested clarification of what the public representatives and
representatives of the population at risk would be asked to do. One
comment urged the agency to refrain from providing precise definitions
for the various terms in Sec. 50.24(a)(7)(i) through (a)(7)(iii) in
order to permit IRB's adequate flexibility in making judgments.
Community consultation is likely to be multifaceted and to use a
number of the mechanisms suggested by the comments. As described
earlier, the IRB needs to provide an opportunity for broad community
discussion. If, for example, there is poor turn-out at a meeting to
discuss the research, an IRB may consider targeting specific

[[Page 51515]]

community representatives for inclusion in an additional meeting, or it
may decide that the research was not found by the community to be
objectionable. The IRB is responsible for listening and considering the
community's support, concerns, etc., and then ultimately deciding
whether the investigation should be modified, approved, or disapproved.
The community is expected to provide input to the IRB on its support
for or concerns about the research activity.
65. A number of comments requested clarification on who is
responsible for the community consultation and disclosure requirements
contained in Sec. 50.24(a)(7)(i) through (a)(7)(iii). Most comments
suggested that the IRB should be responsible for reviewing and
approving the content and method of consultation and disclosure; the
sponsor should be responsible for developing the plan for consultation
with the community and for disclosure and provide this information to
the IRB to review for adequacy.
Although a sponsor may provide to an IRB model information for use
in consultation with the community and for disclosure, just as it may
now provide a model consent form for a clinical investigation, it is
the responsibility of the IRB to ensure the adequacy of the community
consultation and disclosure requirements contained in
Sec. 50.24(a)(7)(i) and (a)(7)(ii).
66. Another comment recommended that the sponsor and clinical
investigator should pay for the costs associated with the disclosure
requirements.
The agency does not dictate the entity responsible for the costs
related to research. However, the agency anticipates that the sponsor
would normally incur the costs associated with disclosure to and
consultation with the community.
67. Several comments on Sec. 50.24(a)(7)(ii) suggested that for
multicenter trials, disclosure be required once for each metropolitan
area and that the disclosure be made by the sponsor or a designated
institution in a notice that would list all institutions,
investigators, and IRB contacts.
The agency would not object to such centralized disclosure if all
of the responsible IRB's agreed that this is appropriate and
acceptable.
68. Another comment suggested that instead of requiring disclosure
prior to the commencement of the study, disclosure occur at periodic
time intervals (e.g., every 2 years) and include a public notice of
general issues, specific projects, results of the research, and permit
public input.
It is the responsibility of the IRB to consider how to maintain the
flow of information to the community. In addition to requiring
disclosure to the community prior to the initiation of the clinical
investigation, the IRB may determine that it is appropriate to require
further disclosure at periodic intervals of time.
69. Another comment requested that the regulation specifically ban
``general disinformation campaigns'' by sponsors performing the
research.
The agency thinks that such a ban is unnecessary and that IRB
involvement in the disclosure process helps to eliminate the
possibility that biased or misleading information will be disseminated.
The information disseminated will be reviewed by the IRB to ensure its
adequacy and balance.
70. A number of comments were opposed to the requirements for
disclosure contained in Sec. 50.24(a)(7)(ii). The comments suggested
that they would take an exhaustive amount of time; could prevent
valuable research because the investigator and institution could be
targets of a poorly informed community; the investigator may not be the
best individual to discuss the study; they could cause persons to not
seek care; they would be burdensome for noncommercially sponsored
studies; for parties with an interest in the research, a requirement
for disclosure could lead to either a dishonest or incomplete
disclosure of information; the regulation requires disclosure of less
information than that which would be given to a research subject; that
it is essential to include information about financial and economic
incentives for the research; and that it is essential to permit public
participation in the disclosure sessions.
As discussed previously, it is the IRB's responsibility to
determine the information to be disclosed. As described in the preamble
to the proposed rule, the IRB should consider how best to publicly
disclose, prior to the commencement of the clinical investigation,
sufficient information to describe the investigation's risks and
benefits, e.g., relevant information from the investigator's brochure,
the informed consent document, and investigational protocol. Initial
disclosure of information will occur during the community consultation
process. Disclosure of this information to the community will inform
individuals within the community about the clinical investigation and
permit them to raise concerns and objections.
71. Another comment suggested that the release of confidential
information required by this section could serve as a disincentive for
sponsors to conduct the research and that it would create a precedent
that could affect companies not otherwise affected by the regulation.
The agency disagrees with this comment. While it is true that much
information relating to clinical investigations is normally treated as
confidential by sponsors, the agency believes that when a sponsor
chooses to invoke the exception from informed consent contained in this
rule that it is essential that reasonable disclosure occur to the
community. The agency believes that the benefit to a sponsor of
invoking the rule will outweigh concerns that a sponsor will have about
disclosing information about the investigation. Because this disclosure
is made only when the exception from informed consent is invoked, it
will not create any precedent for companies not invoking the exception.
The agency notes that sponsors release research information to
investigators and IRB's (for example, through the protocol and
investigators brochure) and to potential subjects in the research
through the informed consent process and informed consent form; this
rule states that the same information should be released to the
community so it can be informed as it considers the research.
FDA believes that American Indian and Alaska Native Tribal
governments and communities currently require both presentation of the
research protocol and reporting results to the community before they
permit any research to occur on their reservation. Recent Phase 2 and
Phase 3 trials of several vaccines (e.g., Haemophilus B, Hepatitis A,
and rotavirus vaccines) have been done on reservations under those
rules by the pharmaceutical companies sponsoring the research. Under
this rule, no company is required to release additional information to
a community if it does not want to have a waiver of consent for its
emergency research.
72. One of these comments stated that information is a property
right and to require that it be surrendered without compensation may
violate the Fifth Amendment of the Constitution.
The agency disagrees with this comment. The Fifth Amendment
requires that no private property be taken for a public purpose without
just compensation. (U.S. Constitution, Amendment V.) One factor used to
determine whether there has been a taking is whether the action
interferes with the reasonable investment backed expectations of the
owner of the alleged

[[Page 51516]]

property right. (Kaiser Aetna v. United States, 444 U.S. 164, 175
(1979).) Where a voluntary submitter of information is aware of the
conditions under which the information must be disclosed, the submitter
gains an economic advantage related to the submission (such as
registration), and the disclosure is rationally related to a legitimate
government interest, there is no taking. (Ruckelshaus v. Monsanto Co.,
467 U.S. 986, 1007-8 (1984).) Under this rule, the disclosure is
directly related to protecting the individual members of a community
that may be involved in the clinical investigation without informed
consent by providing the community with advance notice of the nature of
the investigation and the possibility that they may be involved in the
clinical investigation without their informed consent. Furthermore, the
regulation provides a mechanism under which the sponsor may perform the
clinical investigations and sets the conditions under which the
disclosure will occur. Therefore, the regulation serves as advance
notice that prevents a sponsor from having any reasonable investment-
backed expectation concerning the information and, thus, there is no
unconstitutional taking.
73. A number of comments raised questions about
Sec. 50.24(a)(7)(ii) including: what criteria would be used to
determine that disclosure was adequate; when is the disclosed
information to be provided to FDA; what is meant by ``sufficient'' and
``relevant''; whether it is sufficient prior to the study to simply
post a notice on the bulletin board; who determines the adequacy of the
disclosure; whether this places an obligation to ``disclose'' or to
``disseminate'' information to the community; what this disclosure is
supposed to accomplish. Clarification was requested as to the method
and scope of disclosure.
It is the responsibility of the IRB to determine the
``sufficiency'' of the information to be disclosed. The agency advises
that this information could include, but may not necessarily be limited
to, the information that is found in the informed consent document, the
investigator's brochure, and the research protocol. The obligation to
disclose information includes an obligation to disseminate information
to the community. The purposes of disclosure are to provide community
confidence in the role of the IRB and in its decisionmaking capability,
to permit the community to express its concerns and possible objections
to the research, and to inform the community so that it is aware that
the research is to be conducted involving individuals from the
community.
74. Another comment suggested that FDA and DHHS should provide
IRB's with copies of disclosure forms.
The agency disagrees. It is the IRB's responsibility to determine
the method for disclosure and information to be disclosed. A ``form''
would stifle IRB creativity and flexibility.
75. Comments on Sec. 50.24(a)(7)(iii) suggested that the regulation
specifically include the requirement that the underlying data be
disclosed following the end of the study; another suggested that
product approval decisions should be based on compliance with this
requirement as well as the timeliness of disclosure.
The agency does not think that these comments require a change in
the regulation. The agency thinks that it is necessary to provide
comprehensive summary data from the completed trial to the research
community in order to permit other researchers to assess the results of
the clinical investigation. The agency thinks that there must be a
scientific need to conduct clinical investigations involving subjects
who are unable to consent; if previous investigations have already
provided the scientific answer, this should be shared broadly with the
research community. Sufficient information may be contained in a
scientific publication of the results of the completed investigation;
in other instances, it may need to be supplemented by additional
information. The agency has modified Sec. 50.24(a)(7)(iii) to clarify
that the information to be disclosed is to include the demographic
characteristics (age, gender, and race) of the research population.
In response to the suggestion that product approval decisions
should be based on compliance with this requirement, the agency notes
that it has a variety of compliance procedures that it may use to
enforce this disclosure requirement.
76. Comments opposed to this disclosure requirement suggested that
it would jeopardize the ability to publish the results of the research
in peer review journals; it would foster unscientific conclusions
without peer review; an investigator cannot control the peer review
process to ensure publication; it could negatively influence future
trial recruitment and force a sponsor to disclose proprietary
information. Several comments suggested that in multicenter studies,
one institution may get a negative result, while another may get a
positive result; thus, disclosure could be misleading. Comments
suggested that updating the disclosure could be burdensome and that the
disclosure itself could be considered dissemination of off-label use
information and advertising. Another comment questioned the need for
such disclosure because the community would have no opportunity to
modify the research; another commented that the disclosure would be so
delayed and the community to which the disclosure would occur has such
insufficient knowledge to understand the disclosure, that the
disclosure would be meaningless.
Some comments requested that the agency define what and how
disclosure is to be accomplished; what is ``sufficient'' and what would
constitute the ``scientific community.'' One comment questioned whether
the information that would be disclosed to the community and
researchers would differ.
The comments opposed to this disclosure requirement illustrate a
need for the agency to clarify what is intended by this section. For a
multicenter investigation, the agency anticipates that the sponsor and/
or lead investigators will be responsible for analyzing the results of
the overall investigation, including the demographic characteristics of
the research population, and that these results will be published (or
reported in the lay press) within a reasonable period of time following
completion of the investigation. Publication in a scientific journal or
reports of the results by lay press, that would be supplemented upon
request by comprehensive summary data, will enable the research
community, e.g., researchers not connected to the clinical
investigation, to learn of the research's results. Following
publication, the IRB will be responsible for determining appropriate
mechanisms for providing this information, possibly supplemented by a
lay description, to the community from which research subjects were
drawn. The usual rules of marketing and promotion apply to the
disclosure of this information. The agency notes that it is common for
the results of research to be reported in the lay press and published
in peer reviewed journals.
77. One comment noted that the comment in the preamble that there
would be a need for fewer subjects if disclosure took place did not
recognize the possible need for replication of the research--a sound
scientific principle.
In the preamble to the proposed rule, the agency stated that:
``[b]y broadly sharing the results of the research with the scientific
community, there may be less need to replicate the research; therefore,
fewer subjects may be needed

[[Page 51517]]

to obtain the same level of scientific knowledge and to advance
emergency medicine.'' The agency recognizes that there is frequently a
need to replicate research in order to verify its findings. The agency
thinks, however, that broadly sharing both positive and negative
results of research with the scientific community may reduce or
eliminate unnecessary duplication of research that has been conducted
and verified by others.
7. Section 50.24(a)(5)(iv)--Data Monitoring Committees
A number of comments on proposed Sec. 50.24(a)(5)(iv), which has
been renumbered Sec. 50.24(a)(7)(iv) in this final rule, supported the
requirement for the establishment of an independent data monitoring
committee. These comments also requested clarification of the
requirement and offered various suggestions. A discussion of these
comments and the agency's response follows.
78. Editorial changes were suggested to this section to clarify the
function of the data monitoring committee.
The regulation has been changed to clarify that the purpose of the
data monitoring committee is to exercise oversight of the clinical
investigation. In addition, on the agency's own initiative, the agency
has changed ``data and safety monitoring board'' to ``independent data
monitoring committee'' to conform to wording used in the international
community.
79. Clarification was requested on the function, nature, authority,
and responsibility of the committee. One comment requested citations to
reference materials on data monitoring committees; another suggested
that the regulation reference FDA's ``Guideline for the Monitoring of
Clinical Investigations'' (53 FR 4723). One comment questioned whether
the committee was simply advisory or whether it would have authority to
halt a study. Other comments requested advice on the appropriate
composition of the committee and another requested that FDA define its
minimum size and expertise.
A number of comments requested clarification as to who is
responsible for establishing and operating the data monitoring
committee. One comment suggested that if it is the responsibility of
the sponsor to establish the committee, then the term ``independent''
needs to be defined. Several comments noted that if the responsibility
for establishing the committee changes, depending upon whether the
study is multicenter with a commercial sponsor or a single center,
noncommercially sponsored study, the circumstances for this shift in
responsibility must be clearly described. Another comment asked for
clarification as to who is responsible for establishing ``the
preestablished stopping rules'' and how these rules are defined.
Several comments suggested that it should be the responsibility of the
principal investigator and/or the sponsor of the research to convene
the committee. Another comment suggested that if it is the
responsibility of the sponsor to convene the committee for multicenter
studies, it should be explicitly stated in the regulations.
A number of suggestions were given for how the committee should be
composed and its functions. The agency also received suggestions for
alternatives to the establishment of such a committee. Several comments
suggested that the IRB be responsible for approving the composition of
the committee based on the complexity, size, and risks associated with
the study. Others suggested that the committee should be composed of
specific types of individuals, including scientists, community members,
IRB representatives without a conflict of interest, data management
representatives, biostatisticians, and noninvestigator clinicians.
Others suggested that a link be created between the committee and the
IRB and that specific reporting requirements between the two entities
be established so that the IRB can have the necessary information to
terminate or modify the study.
The agency recognizes that there is no clear consensus within the
scientific community regarding the optimal model for data monitoring
committees. It is not the intention of the agency to settle the debates
that are ongoing in the scientific community at this time. Rather, the
agency recognizes that there is diversity in this area; the role,
functions, and responsibilities of data monitoring committees are
evolving, and it may be the case that there is no single model that is
optimal in all circumstances. The data monitoring committee is
established by the sponsor of the research, as an advisory body to the
sponsor. An independent committee is constituted of individuals not
otherwise connected with the particular clinical investigation. A
variety of expertise is required for an effective data monitoring
committee. Typically included are clinicians specializing in the
relevant medical field(s), biostatisticians, and bioethicists. The data
monitoring committee receives study data on an ongoing basis on a
schedule generally defined in the investigational protocol; based on
its review of the data it may recommend to the sponsor that the
clinical investigation be modified or stopped. In effect, it is
responsible for making sure that continuing the investigation in its
current format remains appropriate, on both safety and scientific
grounds. A number of reasonable models for establishment and function
of these committees are described and discussed in S. Ellenberg, N.
Geller, R. Simon, S. Yusuf (editors), Practical issues in data
monitoring of clinical trials (Proceeding of an International Workshop)
Statistics in Medicine, vol. 12; 1993. If a sponsor accepts a data
monitoring committee's recommendation to stop the investigation or to
institute a major modification of the trial, the sponsor is required to
notify FDA and all participating investigators and IRB's in a written
IND or IDE safety report within 10 working days after the sponsor's
initial receipt of the information. (See Secs. 312.32, 312.56(d), and
812.150(b)(1)).
Protocols frequently contain statistical guidelines for permitting
trials to stop prior to completing the protocol-specified accrual and
followup, on the basis of definitive efficacy or safety differences
between the treatments being compared.
80. Comments opposed to this requirement mainly cited concern that
for single project/single institutional studies without a commercial
sponsor, the cost and resources required for establishing such a body
would be prohibitive and, therefore, important research would not be
done. Another comment suggested that for noncommercially funded
studies, the agency permit the investigator/sponsor to request a waiver
of the requirement to FDA. If such a waiver were granted, timely data
summaries could be submitted to FDA for review.
The agency disagrees with these comments. Trials of life-
threatening conditions may discover favorable or adverse effects on
survival during the trial. Requiring a data monitoring committee will
help ensure that if it becomes clear that the benefits of the
investigational intervention are established, or that risks are greater
than anticipated, or that the benefits do not justify the risks of the
research, the investigation can be modified to minimize those risks or
the clinical investigation can be halted. The data monitoring committee
is established by the sponsor of the research, as an advisory body to
the sponsor. It is the appropriate role of the sponsor, not FDA, to
receive and evaluate a data monitoring committee's

[[Page 51518]]

recommendation. The agency thinks that a data monitoring committee is a
very necessary protection for the human subjects participating in this
research. The agency thinks that the cost of operating such committees
does not need to be prohibitive and that the cost is justified by the
protections provided by having such a committee.
81. Others commented that the requirement for a data monitoring
committee is unnecessary given that these studies already will have
oversight by FDA and the IRB, both of which are independent of the
research, as well as by the sponsor and the clinical investigator.
The agency disagrees. The FDA, IRB, and research sponsor, unlike
the data monitoring committee, do not receive outcome data from the
clinical investigation on an ongoing basis. Thus, oversight by these
entities does not substitute for the requirement for a data monitoring
committee.
82. Another comment pointed out that there was no need for such a
committee for nondrug and nondevice studies if these involved no more
than minimal risk.
This regulation is applicable only to clinical investigations
involving products regulated by FDA.
83. One other comment suggested that this requirement would be
unduly burdensome unless the sponsor paid for the cost of establishing
and operating the committee (including paying for the salaries of
members on the committee).
As discussed previously, FDA does not prescribe what entity pays
for particular aspects of clinical research and review. However, if, as
previously described, the data monitoring committee is established by
the sponsor of the research as an advisory body to the sponsor, the
agency believes that it is likely that the sponsor will pay the cost of
establishing and operating the committee.
84. Another comment suggested that the make-up of the data
monitoring committee should not be left to the sponsor or clinical
investigator to decide and that ``independent'' should be defined as
``separate'' from the research team and sponsor. Another comment noted
that financial interest is only one aspect of what constitutes a
conflict of interest and that the preamble to the final rule should
clarify both terms when describing what constitutes an ``independent''
committee.
The agency believes that the 1993 Statistics in Medicine
publication of the proceedings of an international workshop (previously
referenced) will assist sponsors in establishing appropriate data
monitoring committees. As previously discussed, a variety of expertise
is required for an effective data monitoring committee; the agency
believes that it would be inappropriate for it to dictate the specific
make-up of each such committee. In the preamble to the proposed rule,
the agency defined ``independent'' to mean that the committee would be
composed solely of individuals who have no financial interest in the
outcome of the clinical investigation, and who have not been involved
in the design or conduct of the investigation. The agency does not
think that further clarification of ``independent'' is needed, but
other factors can certainly be taken into consideration in individual
cases.
85. One comment stated that the data monitoring committee should be
charged with monitoring the makeup of the study population to ensure
that it does not disproportionately consist of disadvantaged groups.
There is nothing to prevent a data monitoring committee from
performing this type of monitoring. It is the responsibility of the
sponsor to determine the scope of the data monitoring committee's
responsibilities.
86. Some comments suggested alternatives to requiring the creation
of a data monitoring committee, including requiring more frequent
continuing review by the IRB or permitting a sponsor's monitor to
perform the function. For noncommercially funded studies, it was
suggested that the agency permit the IRB, with scientific and
statistical consultants if needed, to perform the function.
An IRB, as well as a sponsor's monitor, may not have access to
study data on an ongoing basis and may not have the variety of
expertise required for an effective data monitoring committee. If an
IRB, a subcommittee of the IRB, or some other preexisting institutional
committee were to serve as a data monitoring committee, it would need
to be constituted as a data monitoring committee when it functions in
that capacity. The agency thinks that the duties and scope of
activities of an IRB and a data monitoring committee are quite
different and that it is important for separate entities to be
established. The agency would not object, however, to an already
established committee, such as an IRB, serving as a data monitoring
committee as long as that committee was constituted to perform the
duties of a data monitoring committee and operated as such separately
and distinctly from its IRB activities.
87. As described previously, the agency has added a new section,
Sec. 50.24(a)(7)(v), to provide an additional protection to research
subjects. This new section clarifies that if obtaining informed consent
is not feasible and if a legally authorized representative is not
available, the investigator will attempt to contact a family member of
the subject to determine whether the family member objects to the
subject's participation in the clinical investigation.
8. Section 50.24(a)(6)
88. Several comments were received on Sec. 50.24(a)(6). One comment
questioned whether the statement ``obtaining such consent may be
feasible for some subjects'' referred to a circumstance in which
obtaining consent may become feasible.
This comment did not take into account Sec. 50.24(b). Section
50.24(b) concerns providing information to the subject, representative,
or family member at the earliest feasible opportunity. Section
50.24(a)(6) is included to cover those instances where it may be
feasible to obtain informed consent from the individual subject or
subject's representative or contact a family member prior to entry into
the clinical investigation.
89. Two comments suggested specific wording changes to acknowledge
the IRB's responsibility to review informed consent procedures. One
suggested that this section be reworded to state:

The IRB has reviewed and approved informed consent procedures
and an informed consent document for subjects or their legal
representatives in situations where use of such procedures and
documents is feasible.

The agency has incorporated wording similar to that suggested into
the regulation. It is appropriate to recognize the informed consent
process, and not just the document, as requiring IRB review and
approval. In addition, in order to help ensure that the family member
has sufficient information to make a decision about a subject's
participation in a trial, the agency has added a sentence to the end of
Sec. 50.24(a)(6) that states ``[t]he IRB has reviewed and approved
procedures and information to be used when providing an opportunity for
a family member to object to a subject's participation in the clinical
investigation consistent with paragraph (a)(7)(v) of this section.''
The agency anticipates that these procedures and information will
likely parallel those approved by the IRB for use in obtaining informed
consent from subjects or their legally authorized representatives.

[[Page 51519]]

90. A second comment suggested that this section be replaced with
the following:

The IRB has reviewed and approved: (i) the informed consent
document and procedures to ask for informed consent by subjects or
legally authorized representatives when obtaining such consent may
be feasible for some subjects, (ii) the information provided and
process to ask for a decision by subject or legally authorized
representative to continue or discontinue participation after the
research has begun, (iii) the information provided and procedures
for consultation with representatives of the community, (iv) the
information provided and procedures for public disclosure before the
research, and (v) the information provided and procedures for public
disclosure of the results of the research. All documents and
procedures should also be submitted to the FDA for review.

This modification would require both the IRB and FDA to review and
approve all documents or procedures that give information to the
public, subjects, or representatives. The comment suggesting this
modification notes that this is currently required for all nonemergency
IND and IDE research.
The language suggested in this comment appears to duplicate
requirements already contained in the regulation, that is: the
requirement for review of informed consent documents is already
contained in Sec. 50.24(a)(6); the requirement for review of
information concerning the subject's ability to discontinue
participation in the research is contained in Sec. 50.24(b); and the
requirements for review of information used during consultation with or
disclosure to the community are contained in Sec. 50.24(a)(7)(i) to
(a)(7)(iii). FDA has confidence in the IRB review process and does not
think that it is necessary for all of these documents and procedures to
be submitted to FDA for its review. The agency notes that conforming
amendments to this regulation require that a copy of the information
publicly disclosed under Sec. 50.24(a)(7)(ii) and (a)(7)(iii) be
submitted to the IND or IDE file and to Dockets Management Branch. The
agency further notes that the statement that FDA currently requires all
of these documents and procedures to be submitted for its review for
all nonemergency IND and IDE research is incorrect. Rather, it is the
IRB that traditionally reviews information that is to be provided to
the research subject; the requirements for consultation with and
disclosure to the community have not been previously required.
9. Section 50.24(b)
91. A number of comments were received on Sec. 50.24(b) that
suggested clarifying or tightening the requirement for informing
subjects or their legal representatives. One comment recommended that
the agency change the wording from ``at the earliest possible
opportunity'' to the ``earliest feasible opportunity.'' Another comment
suggested that the timeframe for notification was too open-ended and
that there should be a specific time limit.
The agency agrees with the wording change and has incorporated it
into the regulations. The term ``feasible'' incorporates the idea of
``practicability'' and recognizes that in some instances it may not be
feasible to provide information to the subject (e.g., if the individual
does not survive or is mentally incompetent), and to the subject's
legal representative or family member (if the identity of the subject
is never determined). The agency also thinks that the phrase ``at the
earliest feasible opportunity'' establishes a reasonable time limit.
92. Another comment suggested deleting the initial phrase ``when
possible and,'' noting that if the subject does not survive and no
representative is found, then there will be no ``opportunity'' for a
debriefing--thus, the initial phrase is not needed.
The agency agrees with this comment and for the reasons addressed
in the previous response, has deleted this initial phrase from the
regulation.
93. One comment suggested that the regulation require that if a
representative is told and the subject's condition improves, the
subject must also be informed as soon as possible. Two comments stated
that if the subject dies, the subject's legal representative or family
member must be provided with this information.
The agency agrees with these comments and has modified
Sec. 50.24(b) to state:

If a legally authorized representative or family member is told
about the clinical investigation and the subject's condition
improves, the subject is also to be informed as soon as feasible. If
a subject is entered into a clinical investigation with waived
consent and the subject dies before a legally authorized
representative or family member can be contacted, information about
the clinical investigation is to be provided to the subject's
legally authorized representative or family member, if feasible.

94. A few comments suggested that Sec. 50.24(b) be revised to
require documentation that the subject, authorized representative, or
family member, were informed of the research. Another comment suggested
that the agency require a signed consent document for continued
participation in the research.
The agency thinks that it may not always be possible to develop a
meaningful informed consent document for continued participation in the
research, because the relevant information may vary significantly
depending upon when it becomes feasible to provide the information to
the subject or legally authorized representative. The agency is,
therefore, not requiring that such a form be developed. The agency
notes, however, that Sec. 50.24(a)(6) places the responsibility on the
IRB to review and approve ``informed consent procedures and an informed
consent document'' for use with subjects or their legal
representatives, and procedures and information to be used in
consultations with family members, in situations where use of such
procedure is feasible. Thus, a consent form will have been reviewed and
approved for use in the clinical investigation. The agency has modified
the wording in Sec. 50.24(b) to specify that the ``information
contained in the informed consent document'' is to be provided to the
subject, legal representative, or family member. This will help to
ensure that adequate information is provided to the subject, legal
representative, or family member upon which a judgment can be made as
to whether to continue or discontinue the subject's participation in
the investigation.
It is up to the IRB to determine whether it is possible or
desirable, given the nature of the clinical investigation, to have an
actual document that could be signed for continued participation in the
investigation. The agency notes that such a document, that would be
signed after entry into an investigation, would not constitute consent
for what had already occurred; it could, however, serve to document
that the subject consented to continued participation in the
investigation. The agency notes that Secs. 312.60 and 812.140 require
the clinical investigator to document data pertinent to each individual
in the investigation. This documentation should include information
that the subject, legally authorized representative, or family member
was informed of the subject's inclusion in the clinical investigation,
the details of the investigation, and other information contained in
the informed consent document.
95. One comment on the subject's ability to discontinue
participation in the research suggested that Sec. 50.24(b) be reworded
to state:

[[Page 51520]]

The subject or legally authorized representative should be
presented with three options: continue fully, continue the
intervention (if it is still taking place) but do not include the
subject's data in the research database or results, or discontinue
both the intervention and the use of the subject's data. The
researcher will track the percentage of subjects or representatives
choosing each option.

FDA regulations (see, for example, Sec. 312.62 and
Sec. 812.140(a)(3)) require investigators to prepare and maintain
adequate case histories recording all observations and other data
pertinent to the investigation on each individual treated with the drug
or exposed to the device. The agency needs all such data in order to be
able to determine the safety and effectiveness of the drug or device.
The fact of having been in an investigation cannot be taken back. Also,
if a subject were able to control the use (inclusion and exclusion) of
his or her data, and particularly if the clinical investigation were
not blinded, the bias potential would be immense. Thus, the agency
rejects this comment because it could prevent FDA from learning of an
important effect of the product and significantly bias the results of
the investigation.
96. One comment noted that in cases where withdrawal from a study
would be life-threatening, FDA might consider additional guidance on
counseling of subjects who have regained competence regarding their
remaining in the study. Another comment noted that in some cases, a
subject cannot be withdrawn from the study, particularly in the case of
an implanted device, without some degree of medical harm--that is, the
possibility of additional risk for the subject due to its removal. In
this case there is a ``penalty'' for withdrawal from the research.
In all clinical investigations, when appropriate, it is the
responsibility of an investigator to advise the subject of the
consequences of a subject's decision to withdraw from the investigation
and explain procedures for orderly termination of participation by the
subject. (See Sec. 50.25(b)(4)). If withdrawal from an investigation
would or could be life-threatening, this consequence would need to be
conveyed to the subject. The agency acknowledges that for certain
interventions, such as implantation of an investigational device, there
may be a serious consequence following a subject's decision to
discontinue participation in the research. Similarly, for an
investigational drug that cannot be halted immediately without medical
consequences, the subject will need to be advised of the consequences
of a decision to withdraw and procedures for withdrawal that would
minimize risks to the subject.
10. Section 50.24(d)
A number of comments expressed concern about Sec. 50.24(d)
requiring a separate IND or IDE for studies conducted under Sec. 50.24
if an IND or IDE already exists. Others expressed concern about
requiring an IND or an IDE for products that have received FDA approval
for other uses.
97. One comment suggested a modification to the wording of
Sec. 50.24(d) to state that: ``[s]uch IND or IDE should only include
enough detail to satisfy the administrative oversight responsibilities
of appropriate FDA officials.''
The agency disagrees with this suggestion. The information that is
required to be in an IND or IDE is the information that is needed by
the agency to conduct an adequate review of the application. As
described in more detail below, if an IND or IDE exists, the separate
application does not need to duplicate, and the sponsor does not need
to resubmit, information that is contained in the existing IND or IDE;
the separate application will need to reference the existing IND or
IDE, contain a protocol for the clinical investigation that includes a
description of how the investigation proposes to meet the conditions of
this regulation, and contain only the study-specific information
required by Secs. 312.23, 812.20, and 812.25, as appropriate.
98. A number of comments suggested alternative approaches to the
requirement contained in Sec. 50.24(d) for products that have received
marketing approval or for which there already exists an IND or IDE,
noting that for these studies this requirement would be unduly
burdensome, would create the need for unnecessary paperwork, and could
effectively prohibit much needed research. One comment suggested that
the agency limit the scope of this requirement or consider an
alternative for single-center studies under which an IRB can waive
consent if the investigator has informed the appropriate branch of FDA
of the proposed study at least 30 days before submission to the IRB to
allow FDA time to submit its views on the study for consideration by
the IRB. This comment argued that such a requirement would provide
sufficient opportunity for FDA involvement, while at the same time
permit a focused FDA review, consuming fewer resources than would the
review of an IND or IDE for each study. Other comments suggested that
the agency has ample authority under existing IND and IDE regulations
to require strict adherence to the 30-day review period and that the
agency should simply require that emergency research protocols be
clearly identified as such, submitted to the agency under an existing
IND or IDE, and be unable to commence until 30 days after submission.
These comments argued that this would meet the objective of the
regulation without adding additional administrative burdens to the
sponsor or investigator.
These comments may not appreciate why the agency is requiring the
submission of an IND or IDE for each clinical investigation and the
information that must be contained in such an IND or IDE. The
submission of a separate IND or IDE will ensure that FDA reviews the
application before the study may proceed. FDA review of the application
will enable the agency to assess whether the available treatments for
the condition are unproven or unsatisfactory, whether the intervention
is reasonable, whether the study design will provide the information
sought, and whether other conditions of the regulations are met. The
amount of information needed in the application will differ depending
upon the particular intervention. If an IND or IDE exists, the separate
application does not need to duplicate, and the sponsor does not need
to resubmit, information that is contained in the existing IND or IDE;
the separate application will need to reference the existing IND or
IDE, contain a protocol for the clinical investigation that includes a
description of how the investigation proposes to meet the conditions of
this regulation, and contain only the study-specific information
required by Secs. 312.23, 812.20, and 812.25, as appropriate.
If the investigation involves a product that has received marketing
approval and the use is within the product's approved labeling, and
without dosage or schedule change if for a drug product, the protocol
may simply need to be accompanied by the product's approved labeling
and a description of how the investigation proposes to meet the
conditions of this regulation; no toxicology or manufacturing controls
or chemistry information may need to be submitted. By submitting this
information to the agency for review, the dual review by both FDA and
an IRB will provide additional protections to the subjects of this
research. The agency does not think that this requirement is unduly
burdensome, creates unnecessary paperwork, or would prohibit needed
research.
If the clinical investigation involves a product that has received
marketing

[[Page 51521]]

approval, but involves a route of administration or dosage level or use
in a subject population or other factor that significantly increases
the risks (or decreases the acceptability of the risks) associated with
the use of the product, or if the investigation involves an
investigational product for which an IND or IDE does not exist, then
the IND or IDE would need to include information to support the altered
conditions of use, including toxicology, chemistry, and clinical
information, as appropriate.
99. Another comment suggested that the agency should: (1) Include a
mandatory internal ``ethics consult'' of the protocol and informed
consent (this would necessitate requiring the submission of proposed
informed consent documents with the IND/IDE application); (2) ensure
that data on these submissions are captured in a readily retrievable
form for future analysis and reporting so that information on the types
and numbers of such submissions will be available; (3) be able to
provide names and contact information for IRB's reviewing these
protocols to ensure communication among these IRB's; and (4) respond
actively in writing to any submission under these regulations either
placing the study on ``clinical hold'' or indicating that the agency's
review has been completed. This would ensure that the agency has
completed its review before the study is permitted to proceed.
The agency's response to each of these suggestions follows: (1) The
agency believes that it would be inappropriate to mandate an internal
agency ``ethics'' consultation on each protocol proposing to invoke
this exception from informed consent. It is within the province of the
IRB to determine the ethical acceptability of a proposed clinical
investigation. The agency does intend, however, to periodically review
actions on these protocols to help ensure that the rule is implemented
consistently and appropriately throughout the agency. The agency notes
that under the IDE regulations the agency requires the submission of
the proposed informed consent documents with the IDE application. (2)
FDA thinks that it can best monitor the implementation of this rule by
requiring the submission of a separate IND or IDE for these clinical
investigations. By requiring the submission of a separate IND or IDE
for these investigations, FDA expects to be able to provide information
on their type and number. (3) The agency believes that it would be more
appropriate for the sponsor of the research to facilitate communication
among reviewing IRB's, instead of FDA performing this function. (4) FDA
agrees that it should provide a written response to the sponsor
following the agency's review of these protocols. FDA currently sends
written responses following review of IDE's and treatment IND's and
believes that sending letters here will serve as an additional
protection for subjects. The response will serve to document that FDA
has reviewed the clinical investigation and agreed that it may proceed,
and the letters will result in the ability of sponsors to begin these
investigations as expeditiously as possible. The agency has added
language to Secs. 312.20(c) and 812.20(a)(4)(i) to clarify that a
clinical investigation involving an exception from informed consent
under Sec. 50.24 is not permitted to proceed without the prior written
authorization from FDA. FDA will provide such notification 30 days
after FDA receives the application, or earlier.
100. Section 50.24(d) raised a number of questions and caused
confusion concerning its applicability to: Studies designed to compare
the efficacy of two already marketed agents; the study of systems,
processes, and procedures that are not designed to assess the efficacy
of a test agent, but rather to determine the best process or technique
for its use; a study comparing the effect of a standard of care with
the use of no agent at all; and FDA exercising jurisdiction over
studies that do not involve evaluating the safety or efficacy of a
product subject to FDA regulation. One comment recommended that the
regulations be expanded to apply to not only new devices or drugs, but
also to new uses for existing devices and drugs, as well as to new
therapeutic techniques and that researchers be permitted to seek FDA
approval for research on drugs or devices already in use through
alternate forms and/or procedures developed by FDA for this purpose.
This comment incorrectly interpreted the wording in Sec. 50.24(d)
to apply only to unapproved new devices or unapproved new drugs. As
discussed earlier, Sec. 50.24(d) also applies to clinical
investigations involving already marketed products that are regulated
by FDA. This regulation does not apply to research that is outside of
FDA's regulatory jurisdiction--that is, studies involving no product
subject to FDA regulation.
101. A number of examples were provided of studies that purportedly
would have been prevented if an IND or IDE had been required: (1) High
versus low dose epinephrine; (2) interposed abdominal counterpulsation
CPR; (3) saline infusion during trauma; (4) effect of high pressure
ventilation during CPR; (5) studies on sodium bicarbonate during CPR;
(6) studies on MAST trousers during CPR; and (7) comparison of various
intravenous crystalloid solutions in shock-trauma. The application of
this requirement to these types of studies was described, by at least
one comment, as the ``fatal flaw'' in the regulation. Other comments
suggested that the broad scope of this requirement would be wasteful of
sponsor resources in terms of filing the IND and IND annual reports,
wasteful of FDA resources in terms of reviewing such studies, cause
unnecessary paperwork, and would suppress necessary studies.
As discussed previously, the agency believes that it is necessary
to require an IND or IDE for these types of clinical investigations and
it does not believe that this requirement is unduly burdensome or that
it will prevent needed research. The information required in a
sponsor's annual report would not increase because of the requirement
for a separate IND or IDE. The sponsor would simply need to prepare a
separate cover letter and excerpt the information from the other IND's
or IDE's annual report, and file it in the separate IND or IDE.
102. Several comments suggested that the IND/IDE regulations could
be revised to allow for a 30-day review period for those studies that
qualify for this exemption; that sponsors would voluntarily agree to
wait 30 days for agency review of such studies; or that the agency
could place ``on hold'' for 30 days such studies in order to allow for
agency review.
FDA thinks that the most efficient way for the agency to ensure
that these clinical investigations are reviewed by the agency before
they commence is to require the submission of a separate IND or IDE for
that investigation. FDA is concerned that to allow these investigations
to be submitted as amendments to existing IND's or IDE's could be
confusing to sponsors and might lead to these investigations beginning
before FDA review. This is because the agency's current regulations do
not require a 30-day wait for amendments; they can begin immediately
following submission to the agency and receipt of IRB approval. The
agency thinks that this is a simple and nonburdensome mechanism that
achieves an important protection for subjects in this research in which
subjects may be enrolled without informed consent.
11. Section 50.24(e)
103. Most of the comments on Sec. 50.24(e) objected to FDA
modifying

[[Page 51522]]

the traditional reporting/information flow from IRB to clinical
investigator to sponsor and the reverse. These comments requested that
the agency retain this flow of communication in the rule.
The agency disagrees with these comments. Although FDA recognizes
that the sponsor's interaction with the IRB should primarily occur
through the investigator who conducts the clinical investigation, FDA
has never prohibited direct communication between the sponsor and the
IRB when doing so would result in a more efficient flow of information.
For clinical investigations involving medical devices, FDA requires
direct communication between the sponsors and the IRB's in a number of
instances. (See, for example, multiple paragraphs in Sec. 812.150(b).)
The agency thinks that it is appropriate for the IRB to communicate
directly with the sponsor and for the sponsor to communicate directly
with the IRB when this improves efficiency and/or safety, as it does in
this regulation. The agency has amended this section and its related
conforming amendments to specify that the IRB shall document its
findings and provide them promptly in writing to the investigator and
the sponsor of the clinical investigation when an IRB determines that
it cannot approve the investigation because the investigation does not
meet the criteria in the exception or because of other relevant ethical
concerns. The agency thinks that this is the most efficient mechanism
to ensure that both the investigator and sponsor are advised of the
IRB's findings in a timely manner.
104. In a related comment, clarification was requested for studies
in which there is no commercial sponsor and whether it is then the
responsibility of the institution or the individual investigator to
carry out the requirements specified in this section (as well as in the
conforming amendments of Secs. 56.109(g), 312.30, and 312.54).
Whether or not there is a commercial sponsor, each clinical
investigation has a sponsor and it remains the sponsor's responsibility
to carry out the requirements assigned to the sponsor in this section.
(I.e., if the investigation is investigator-sponsored, the investigator
is the sponsor of the research and, therefore, the investigator assumes
all the responsibilities of the ``sponsor.'')
105. Another comment suggested that when an investigator is
proposing a previously IRB-rejected protocol, the investigator is
ethically obligated to disclose the rationale of the earlier rejecting
IRB.
The agency agrees with this comment, but it believes that no change
is needed in the regulations. The requirements in Sec. 50.24(e) will
compel a sponsor to disclose to IRB's that have reviewed or are asked
to review a clinical investigation the findings of an IRB that could
not approve the investigation because the investigation does not meet
the criteria in this exception provided under paragraph (a) of
Sec. 50.24 or because of other relevant ethical concerns.
106. Another comment suggested that in order to avoid delay or
failure to convey information about previously disapproved protocols,
the IRB should submit information directly to FDA.
The agency disagrees with this comment. The conforming amendments
(Sec. 312.54(b) and Sec. 812.47(b)) require a sponsor to monitor these
studies to identify when an IRB determines that it cannot approve the
research because it does not meet the criteria in Sec. 50.24(a) or
because of other relevant ethical concerns, and to promptly provide
this information in writing to FDA. The sponsor is, therefore,
obligated to submit this information promptly to the agency.
107. Another comment suggested that sharing IRB research rejection
information compromises the autonomy of the IRB and that it will make
impartial decision making more difficult.
The agency disagrees and believes that human subject protections
will be enhanced by sharing of this information.
108. A number of comments and questions addressed the phrase
``substantially equivalent clinical trials.'' Several comments noted
that a given sponsor may not be aware of a substantially equivalent
clinical trial proposed by another sponsor; thus, FDA and/or OPRR
should be responsible for ensuring that communication about such trials
takes place. One suggestion was for FDA to establish an on-line
registry at FDA of studies that have applied for waiver of consent;
this registry could be searched by IRB's and investigators to determine
which other IRB's have reviewed the same or substantially equivalent
trials.
The agency intended this requirement to refer to clinical trials
with the same sponsor. The regulation has been modified to clarify this
issue.
109. One comment suggested that the extent of this reporting (of
``disapproval'' information) should be defined in the preamble, with
the minimum content of such a report contained in the regulation.
Existing Sec. 56.109(d), redesignated as Sec. 56.109(e) requires an
IRB to ``notify investigators and the institution in writing of its
decision to approve or disapprove the proposed research activity, or of
modifications required to secure IRB approval of the research
activity.'' It states that ``[i]f the IRB decides to disapprove a
research activity, it shall include in its written notification a
statement of the reasons for its decision.* * *'' The new sentences to
Sec. 56.109(e) requires the IRB to notify the investigator and sponsor
in writing when an IRB determines that it cannot approve the research
because it does not meet the requirements of Sec. 50.24(a) or because
of other ethical concerns. FDA has revised the wording of
Sec. 56.109(e) to make it explicit that this written notification must
include a statement of the reasons for the IRB's determination. The
correspondence from the IRB should contain sufficient information for a
receiving IRB to understand the concerns of the initial IRB.
110. One comment noted that if it is the agency's concern that a
sponsor may minimally modify the rejected proposal (i.e., a
substantially equivalent trial) and submit it to another IRB, that
should be clarified and prohibited. Another questioned whether
``equivalent'' referred to medical conditions, treatments compared,
subject populations, or something else. Another comment questioned
whether ``substantially equivalent'' only applies to other trials with
the same drug/device; if the sponsor subsequently requests an exemption
for a similar trial with another drug in the same class must the
sponsor disclose the IRB findings about the first drug.
By ``substantially equivalent'' the agency means other clinical
investigations that propose to invoke this exception from informed
consent and that involve basically the same medical conditions and
investigational treatments. As noted previously, the agency intends
this requirement to refer to clinical investigations conducted by the
same sponsor.
111. Another comment questioned who is expected to make the
determination that a study is ``substantially equivalent.'' This
comment described a potential situation whereby an IRB rejected a
protocol as written and the sponsor then modified the protocol
according to the IRB's recommendations. This comment, as well as
others, questioned whether, in a multicenter study, the other centers
that approved and initiated the initial protocol would have to review
this trial again.
It is the sponsor's responsibility to determine that a study is
``substantially

[[Page 51523]]

equivalent.'' If, in the scenario described, a protocol invoking this
exception is modified by the sponsor in order to respond to IRB
concerns that it does not meet the criteria in Sec. 50.24(a) of the
exception or because of other relevant ethical concerns, and it is a
multicenter study, then the IRB's written findings are to be disclosed
to other centers that either are, or may be, participating in the
study. If there is a change in a protocol in a multicenter trial, there
is re-review of the protocol by all the IRB's of the institutions
participating in the multicenter trial. If the change is minor, it may
be eligible for expedited review under Sec. 56.110, which permits the
IRB to use an expedited review procedure to review minor changes in
previously approved research during the period for which approval is
authorized. If the change is significant, it would need to be reviewed
by the full committee. It is the sponsor's responsibility to determine
if it has a substantially similar protocol necessitating information
dissemination.
112. One comment noted that the current wording of Sec. 50.24(e)
appeared to require disclosure of IRB disapprovals only to future IRB's
and investigators. This comment suggested that the regulation should
specify that investigators already participating and IRB's that have
already approved the study be notified of an IRB disapproval.
The agency agrees with this comment and has modified Sec. 50.24(e)
accordingly. The agency thinks that this information is relevant to
IRB's that have reviewed and approved the study and that will be
responsible for conducting continuing review of the research as well as
to IRB's that will be asked to review the study. Although this
information may not change an IRB's final determination on the
approvability of a particular protocol, it will allow access to, and
the ability to consider, information that negatively influenced another
IRB.
113. Several comments questioned the timing of IRB review and
submission of the IND. One comment suggested that IRB review precede
the submission of the IND to prevent agency review of studies that
would eventually be found to be unacceptable to the reviewing IRB's.
This comment suggested that the regulations be modified to indicate
that if an IRB refuses to approve the study, the sponsor could request
a pre-IND meeting with FDA to discuss the reasons for the disapproval.
Another comment suggested the opposite, noting that many IRB's will not
consider a protocol under an IND or IDE until after FDA approval
because FDA review includes aspects that are not within the scope of
IRB review. Thus, FDA should agree to review and approve IND's and
IDE's that contain a firm and binding sponsor commitment to local IRB
review. This comment noted that implementation of the Sec. 50.24(a)
provisions will be policed by OPRR and, thus, both FDA and the public
can be ensured that the sponsor's advance commitment will be met. This
comment suggested the following language:

Sec. 312.40(b)(3) For a separate IND submitted under
Sec. 312.20(c), if a sponsor provides a commitment to local IRB
establishment and approval of procedures for compliance with
Sec. 50.24(a).
Sec. 812.30(a)(3) For a separate IDE submitted under
Sec. 812.20(a)(4), if a sponsor provides a commitment to local IRB
establishment and approval of procedures for compliance with
Sec. 50.24(a).
Sec. 50.24(c) [Add the following sentences] The IRB must
document the additional protections provided under subsection (a)(5)
in writing to the sponsor of the research. The sponsor of the
research must share this information with FDA.

The agency does not agree that it should mandate the timing of IRB
and FDA review. As evidenced by the comments, sponsors currently differ
in whether they request FDA or IRB review first. FDA does not believe
it should reduce the sponsor's flexibility to determine the sequence of
IRB and FDA review. The agency notes that FDA may find a clinical
investigation unacceptable or require modifications in an investigation
which, if it had been reviewed by an IRB, would require re-review by
the IRB.
The comment concerning an IRB refusal to approve a study and the
need for a pre-IND meeting does not explain the reason such a meeting
should occur. As described in 312.47(a): ``[m]eetings between a sponsor
and the agency are frequently useful in resolving questions and issues
raised during the course of a clinical investigation. FDA encourages
such meetings to the extent that they aid in the evaluation of the drug
and in the solution of scientific problems concerning the drug, to the
extent that FDA's resources permit.'' Thus, while there is nothing to
prevent a sponsor from requesting a meeting with FDA, it is not clear
that a sponsor would want to meet with the agency to discuss why an IRB
did not approve its investigation.
In response to the comment that FDA should agree to review and
approve IND's and IDE's that contain a firm and binding sponsor
commitment to obtain local IRB review, FDA agrees. FDA will accept a
sponsor's commitment in an IND or IDE application to obtain IRB review
in this situation as it does in others. The agency understands that IRB
review may follow submission and review of the investigation by FDA.
Thus, where an IRB has not yet reviewed and approved the protocol that
the agency has reviewed and allowed to proceed, an IRB's review and
approval, as well as community consultation and disclosure, are then
required prior to subjects entering the investigation.
The agency notes that OPRR does not enforce the provisions in
Sec. 50.24(a) for clinical investigations that are regulated by FDA.
Instead, FDA oversees the quality and integrity of the research that is
conducted under the agency's jurisdiction through its Bioresearch
Monitoring Program. FDA's Bioresearch Monitoring Program includes
inspections of clinical investigators, sponsors, and IRB's to evaluate
whether each entity's obligations are met.
Finally, the agency does not believe there is a need to adopt the
additional language suggested regarding IRB review because the language
is redundant with existing regulations, i.e., the regulations already
require sponsors to obtain the investigator's commitment to obtain IRB
review (see, for example, 312.53(c)(1)(vii)); IRB's are required to
``find and document'' each item under (a), including (a)(6)) (see
Sec. 50.24(a)); and IRB's are required to provide information that has
been publicly disclosed under Sec. 50.24(a)(7)(ii) and (a)(7)(iii) to
the sponsor and the sponsor is required to provide this information to
FDA (see, for example, Sec. 56.109(g), Sec. 312.54(a), Sec. 601.51(d),
and Sec. 812.38(b)(2)). In addition, as previously described, FDA
expects the protocol for the investigation to include a description of
how the investigation proposes to meet the conditions of this
regulation.
114. A number of comments questioned the value of Sec. 50.24(e) and
suggested that it be deleted. The reasons given in these comments
included: its impracticality, its irrelevance to local decision making,
the inappropriate line of communication (previously discussed), and the
precedent that it establishes for requiring public disclosure of IRB
decision-making (potentially leading to extra liability from disclosure
for the IRB). Comments also questioned whether the requirement would
apply to unsponsored research (discussed above), noted that if FDA
needs this information it can request it from the IRB, and asserted
that it is inappropriate for the IRB to apparently review a study and
give feedback to FDA when IRB's depend on FDA to conduct an adequate
preliminary review of such studies. Comments also noted the paperwork

[[Page 51524]]

burden on IRB's (which may need to write a very different type of
document than the one that it would typically write in rejecting a
study), and that this requirement could undermine the authority of the
IRB if it were obliged to report each rejection to FDA. One other
comment questioned the value of this requirement noting that one IRB's
decision to reject a study would have no impact on the substantive,
factual medical and other information available to all IRB's. This
comment noted that the relevance of this evaluation for an IRB that has
already approved a study would be even more untenable and burdensome
and could potentially be disruptive to the sponsor and ongoing studies.
Another comment noted that this requirement is ambiguous and questioned
whether the sponsor would need to provide the report exactly as
provided by the IRB or whether the sponsor could summarize the IRB's
findings. This comment also questioned how FDA would use this
information.
The agency disagrees with these comments. The agency does not think
that this will create an additional recordkeeping burden on IRB's
because these findings are already required to be documented by the IRB
under Sec. 56.109(e) and Sec. 56.115(a)(2). As noted earlier, the
agency has modified this section to require the IRB to provide these
findings to the clinical investigator and to the sponsor of the
research. The agency has a great deal of respect for the IRB system and
for decision-making that occurs by IRB's. Given the nature of this
research, the agency thinks that it is important for entities with
responsibility for allowing these investigations to proceed to consider
IRB concerns related to these investigations. The agency will expect
the sponsor to forward the report exactly as it was provided by the
IRB; however, the sponsor may choose to provide additional relevant
information to the agency along with the IRB's findings. Similarly, if
an IRB chooses to prepare more extensive documentation of its findings
than that which is required by Sec. 56.109(e), Sec. 56.115(a)(2), and
Sec. 56.115(a)(4), there is nothing in this regulation that would
prevent the IRB from so doing.
115. One comment noted that an IRB may reject a study based on the
ethical criticism of a single member. This comment argued that if an
IRB raised a relevant ethical issue, the sponsor, which is the entity
with the greatest legal liability, should evaluate the issue and if the
concern is found to be valid, it should be up to the sponsor to decide
to communicate the issue to other IRB's. This comment suggested that
abridging the sponsor's responsibility will lead to less independent
thinking by IRB's, slower progress in expanding clinical trials, and a
``mass'' of less than well-considered ethical comments being presented
to FDA for its consideration.
The agency intends to monitor and evaluate the implementation of
this regulation on an ongoing basis. While the agency doubts that such
effects will be caused by this requirement, the agency will evaluate
the impact of this requirement on IRB's and the conduct of clinical
investigations. The agency notes that if an IRB ``rejected'' an
investigation on the basis of an argument put forth by a single IRB
member, it would appear likely that member's arguments were persuasive
to the whole IRB.
116. The agency received a number of comments that suggested
editorial or technical changes to clarify the language contained in the
regulations.
The agency has incorporated editorial and technical changes where
the agency thinks that they add clarification to the language in the
regulation. In certain cases, the agency disagreed that the editorial
or technical changes would clarify the language in the regulation.

C. Conforming Amendments

A variety of comments were received on the conforming amendments.
Some of these have been previously discussed. Others, that relate
solely to the conforming amendments, are discussed below.
117. One comment objected to Sec. 56.109(c)(1) which allows an IRB
to waive the requirement that the subject sign a written consent form
if it finds that the research presents no more than minimal risk of
harm to subjects and involves no procedures for which written consent
is normally required outside the research context. This comment noted
that one cannot ensure that informed consent is obtained, if a written
consent form is not signed.
The language contained in Sec. 56.109(c)(1) has been in effect
since 1981 and applies to research that involves no more than minimal
risk of harm to subjects and involves no procedures for which written
consent is normally required outside the research context. This section
does not apply to research conducted under the provisions of this rule.
118. One comment suggested that Sec. 56.109(c)(2) be modified to
include the suggestion that the IRB should seek additional input, as
necessary, from sponsors or other experts to aid them in their decision
making.
The IRB currently is free to consult with anyone that it wants; no
change in the regulation is needed.
119. One comment on Sec. 56.109(d) suggested that the discretion
suggested by the use of the term ``may'' was inappropriate and that
this term should be changed to ``must'' in order to require the
investigator to provide subjects with a written statement. Another
comment questioned whether the proposed Sec. 56.109(d) replaced the
current (d) or extended it.
Proposed Sec. 56.109(d) was taken from the existing IRB regulation;
it was the last sentence in Sec. 56.109(c). Section 56.109(d) became
proposed Sec. 56.109(e) with an additional sentence added at the end.
In writing this conforming amendment, the agency intended new
Sec. 56.109(d) to apply only to Sec. 56.109(c)(1)--that is, to studies
that involve no more than minimal risk and involve no procedures for
which written consent is normally required outside the research
context. The agency has modified Sec. 56.109(d) to make this clear; on
its own initiative, the agency has also corrected a typographical error
in this paragraph. The agency notes that Sec. 50.24(b) describes the
requirements for emergency research.
120. One comment suggested that Sec. 56.109(e) does not match the
intent of Sec. 50.24(e), in that not only the notice of disapproval,
but also the reason and/or concern needs to be provided. This comment
suggested that Sec. 56.109(e) be modified to include the following
sentence: ``The written notification shall include a statement of the
reasons for the disapproval.''
The agency agrees with this comment and had intended that the
reasoning behind the IRB's determination be provided. The agency notes
that it is not only IRB disapprovals, but also an IRB's determination
that it cannot approve an investigation, that triggers this
requirement.
121. Another comment suggested that elsewhere in the regulations,
there is allowance given for discussion between an investigator whose
study has been disapproved and the reviewing IRB. This comment
suggested that similar wording, or clarification, should allow for
sponsor and IRB negotiation.
The agency disagrees with this comment. The purpose of this
requirement is to enhance, not limit, communication of information
between IRB's, investigators, sponsors, and FDA. Sec. 56.109(d),
renumbered as Sec. 56.109(e), continues to state that ``[i]f the IRB
decides to disapprove a research activity, it shall include in its
written notification a statement of the reasons for its decision and
give the investigator an opportunity to respond in person or in
writing.'' There is nothing in this regulation that prevents this

[[Page 51525]]

opportunity for discussion from occurring. It is up to the IRB,
however, to determine when a final determination has been made on a
study.
122. One comment questioned whether Sec. 56.109(e) should be
paragraph (f) (a new paragraph), referring only to documentation of
refusals to approve.
Old 56.109(d) which concerns decisions to approve, disapprove, or
modify research, was renumbered in the proposal as new section
56.109(e). Thus, this paragraph does address documentation of
disapprovals.
123. One comment recommended that the responsibility for
determining when disclosure has occurred be assigned to the IRB's and
that IRB's should be required to notify the sponsor so that the sponsor
could notify FDA. This comment would affect Secs. 56.109(g),
314.430(d), 812.38(b)(2) and 812.47(a).
The responsibility for determining when information has been
publicly disclosed is a dual responsibility of the IRB and sponsor.
Section 56.109(g) requires the IRB to provide a copy of information
that has been publicly disclosed to the sponsor of the research; the
sponsor is responsible for notifying FDA. Sections 312.54(a) and
812.47(a) require the sponsor to monitor the progress of all research
invoking Sec. 50.24 to determine when the public disclosures occur and
to promptly submit copies of the information that has been publicly
disclosed to the IND or IDE file and also to the Dockets Management
Branch.
124. One comment recommended that proposed section 56.111(c) be
deleted, noting that this section is a documentation statement, rather
than an approval criterion. This comment notes that proposed
Sec. 50.24(a) contains similar language requiring such documentation
and, therefore, no benefit is evident in the proposed modification to
Sec. 56.111.
The agency agrees that there is no need for proposed section
56.111(c). Under Sec. 50.24(a), the IRB is responsible for finding and
documenting that each of the safeguards are met; this is also covered
broadly by Sec. 56.111(a)(4).
125. Several comments suggested that Sec. 312.54(a) be modified to
state that the ``sponsor shall document'' rather than ``determine''
when public disclosure has occurred. These comments suggested that
``determine'' could be misconstrued to mean that the sponsor shall
``decide'' what constitutes adequate public disclosure, and that it is
the responsibility of the IRB to make that determination.
The agency agrees that it is the responsibility of the IRB to
determine what constitutes adequate disclosure to the community;
however, it is the responsibility of the sponsor to provide copies of
the information disclosed to the agency. The language in Sec. 312.54(a)
has been modified to clarify that when the sponsor receives from the
IRB information concerning the public disclosures required by
Sec. 50.24(a)(7)(ii) and (a)(7)(iii), the sponsor is required to submit
the information that was disclosed to FDA.
126. One comment recommended that the reference to Sec. 50.23 be
removed from Sec. 312.60 but provided no explanation.
FDA rejects this comment and believes that the reference to
Sec. 50.23 in Sec. 312.60 is needed to identify the various provisions
in the regulations permitting an exception to informed consent. Because
Sec. 50.23 provides different criteria for permitting an exception to
the informed consent requirement, the agency is retaining reference to
this section in Sec. 312.60.
127. One comment questioned the meaning of the modification to
Sec. 314.430 and whether it means that Freedom of Information (FOI)
requests for this information will not be processed, or that requests
for information publicly disclosed under Sec. 50.24(a)(7)(ii) and (iii)
must be submitted to the Dockets Management Branch.
Requests for copies of this public disclosure information are to be
submitted as Freedom of Information Act requests. FDA has amended Sec.
312.130(d), 314.430(d)(2), 601.51(d)(2), 812.38(b)(4), and 814.9 to
clarify that persons wishing to request the publicly disclosed
information in the IND or IDE that was required to be filed with the
Dockets Management Branch shall submit a request under the Freedom of
Information Act. Alternatively, persons wishing to view this
information may visit FDA's Dockets Management Branch (HFA-305), Food
and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD
20857. A special docket, Docket Number 95S-0158, has been established
for this purpose. To facilitate retrieval of information that may
pertain to a single clinical investigation, FDA is specifying that
information submitted to the docket must be identified by the IND or
IDE number.
128. This comment also suggested that Sec. 312.130 be modified by
the addition of

312.130(d) For investigational new drug applications involving
an exception from informed consent under Sec. 50.24 of this chapter,
sponsors are required to submit copies of information that has been
publicly disclosed under Sec. 50.24(a)(5)(ii) and (a)(5)(iii)
[renumbered Sec. 50.24(a)(7)(ii) and (a)(7)(iii)] to the IND file
and to Dockets Management Branch. Copies of this information will be
available to the public from the Dockets Management Branch.

The agency agrees with this comment that it would be clearer if
Sec. 312.130(d) were modified. Consistent with the discussion above,
the agency has amended Sec. 312.130 to add a new paragraph (d) which
contains similar language to that suggested in the comment.
129. On the agency's own initiative, FDA is amending the clinical
hold regulation at Sec. 312.42 to explicitly include a failure to
comply with the requirements in Sec. 50.24 as a reason for clinical
hold. The agency believes this revision will remove any confusion that
may exist regarding the authority to stop, where warranted, an
investigation invoking this rule. The agency does not believe a change
is needed to the device regulation at Sec. 812.30 on disapproving or
withdrawing approval of an IDE because that regulation currently
expressly authorizes FDA to take such action for failure to comply with
``any other applicable regulation or statute, or any condition of
approval imposed by an IRB or FDA.''

D. Preemptive Effect

In developing these rules, FDA considered whether there were
existing State or local legal requirements governing informed consent
that might limit or preclude participation in research in circumstances
that otherwise could be authorized by IRB's acting in accord with these
proposed rules. FDA recognizes that nationally uniform informed consent
requirements governing this type of research could serve to lessen the
current confusion created in the research community by differing
Federal regulations. FDA also recognizes that the existing Federal
Policy for the Protection of Human Subjects, which governs much of this
type of research, currently provides that it does not affect any State
or local laws or regulations that may otherwise be applicable and that
provide additional protections for human subjects. Accordingly, FDA
specifically invited comment on whether there are existing State or
local legal requirements that might limit or preclude participation in
research in circumstances that otherwise could be authorized by IRB's
acting in accord with these proposed rules and whether any such
requirements should be preempted by Federal requirements. As discussed
previously, FDA received limited information on existing State or local
legal requirements that might limit or preclude participation in
research covered by this rule. The agency also

[[Page 51526]]

received a number of comments in favor of the status quo. The
information submitted on existing State or local legal requirements was
insufficient for the agency to justify changing the existing Federal
policy for the protection of human subjects, which governs much of this
type of research, and which currently provides that it does not affect
any State or local laws or regulations which may otherwise be
applicable and which provide additional protections for human subjects.
Thus, the agency does not intend to preempt existing State or local
requirements that provide additional protections for human subjects.

IV. Effective Date

These regulations are effective November 1, 1996. IND's and IDE's
that intend to invoke this rule may be submitted to the agency on or
after the publication date of this rule and must 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.

V. Environmental Impact

The agency has determined under 21 CFR 25.24(a)(8) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.

VI. Executive Orders

A. Executive Order 12606: The Family

Executive Order 12606 directs Federal agencies to determine whether
policies and regulations may have a significant impact on family
formation, maintenance, and general well-being. FDA has analyzed this
rule in accordance with Executive Order 12606, and has determined that
it has no potential negative impact on family formation, maintenance,
and general well-being.
FDA has determined that this rule will not affect the stability of
the family, and particularly, the marital commitment. It will not have
any significant impact on family earnings. The rule would not erode the
parental authority and rights in the education, nurture, and
supervision of children.

B. Executive Order 12612: Federalism

Executive Order 12612 requires Federal agencies to carefully
examine regulatory actions to determine if they would have a
significant effect on Federalism. Using the criteria and principles set
forth in the order, FDA has considered the rule's impact on the States,
on their relationship with the Federal Government, and on the
distribution of power and responsibilities among the various levels of
government. FDA concludes that this rule is consistent with the
principles set forth in Executive Order 12612.
Executive Order 12612 states that agencies formulating and
implementing policies are to be guided by certain Federalism
principles. Section 2 of Executive Order 12612 enumerates fundamental
federalism principles. Section 3 states that, in addition to these
fundamental principles, executive departments and agencies shall
adhere, to the extent permitted by law, to certain listed criteria when
formulating and implementing policies that have federalism
implications. Section 4 lists special requirements for preemption.
Section 4 of Executive Order 12612 states that an executive
department or agency foreseeing the possibility of a conflict between
State law and federally protected interests within its area of
regulatory responsibility is to consult with States in an effort to
avoid such conflict. Section 4 of the Executive Order also states that
an executive department or agency proposing to act through rulemaking
to preempt State law is to provide all affected States notice and
opportunity for appropriate participation in the proceedings. As
required by the Executive Order, States have had, through this rule's
notice of proposed rulemaking, an opportunity to raise the possibility
of conflicts and to participate in the proceedings (section 4(d) and
(e)). Consistent with Executive Order 12612, FDA requested information
and comments from interested parties, including but not limited to
State and local authorities, on these issues of federalism. FDA is not
preempting State law through this rulemaking.

VII. Analysis of Impacts

FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this rule is consistent with the regulatory philosophy and principles
identified in the Executive Order. The agency has determined that this
rule is a ``significant regulatory action'' as defined in section
3(f)(4) of the Executive Order because it raises novel policy issues.
If a rule has a significant economic impact on a substantial number
of small entities, the Regulatory Flexibility Act requires agencies to
analyze regulatory options that would minimize any significant impact
of a rule on small entities. This rule is a deregulatory action insofar
as it will permit research to proceed that could not proceed under
existing regulations, and because relatively few research projects will
need to meet the requirements of this rule. Therefore, under the
Regulatory Flexibility Act 5 U.C.C. 605(b), the Commissioner certifies
that the rule will not have a significant economic impact on a
substantial number of small entities. Therefore, under the Regulatory
Flexibility Act, no further analysis is required.

VIII. Paperwork Reduction Act of 1995

This rule contains information collection requirements that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (Pub. L. 104-13, May 22, 1995), and
that are already approved under Protection of Human Subjects--
Recordkeeping Requirements for Institutional Review Boards, part 56 (21
CFR part 56) under OMB Control No. 0910-0130; Investigational New Drug
Application under OMB Control No. 0910-0014; and Investigational
Devices Exemption Reports and Records, part 812 (21 CFR 812) under OMB
Control No. 0910-0078. Modifications to these approved information
collection requirements are underway or will be made at the time that
each information collection is renewed. The agency believes that this
is appropriate because this rule has only a minor impact on these
existing information collection packages.
One comment was received on the agency's estimate of paperwork
burden. That comment noted that the estimate of 20 sponsored
investigational drug and 10 sponsored device studies that will require
waiver of consent may be correct for multicenter studies sponsored by
manufacturers. However, based on results from an informal survey of

[[Page 51527]]

Emergency Medicine Research Directors conducted in May 1994 and again
in December 1994, there may be a substantial number of single
investigator/single institution studies that will also involve waiver
of consent. The comment, thus, concluded that the agency had
underestimated the total number of studies that will be advanced for
consideration of a waiver of consent.
This comment is correct; the agency did not consider single-
investigator/single-institution studies. In response to this comment,
the agency has estimated that there will be approximately 25 single-
institution studies requiring an IDE and 50 single-institution studies
requiring an IND annually. This paperwork section has been revised
accordingly.
For Protection of Human Subjects--Recordkeeping Requirements for
IRB's under OMB Control No. 0910-0130, FDA has calculated the existing
recordkeeping burden on IRB's required by Sec. 56.115 based on the
estimated number of IRB's and the estimated annual number of hours each
IRB spends in recordkeeping activities. FDA does not believe that this
rule will increase the number of IRB's. However, the agency estimates
that the number of hours for recordkeeping related to studies that
propose to invoke this exception from informed consent will increase
for an estimated 275 IRB's by 5 annual hours per record-keeper. This
will change the estimated recordkeeper burden from 65 to 70 hours
annually for these estimated 275 IRB's.
The newly redesignated and revised Sec. 56.109(e) proposes to
require that an IRB notify in writing the sponsor of the research when
an IRB determines that it cannot approve the research because it does
not meet the criteria in the exception provided under Sec. 50.24(a) of
this chapter or because of other relevant ethical concerns. In accord
with the Paperwork Reduction Act of 1995, the agency discloses that
this rule requires this third party notification.
For Investigational New Drug Application under OMB Control No.
0910-0014, the agency estimates that sponsors will submit an average of
20 studies a year, with an average of 20 clinical investigators each,
that propose to invoke this exception from informed consent and that
sponsor-investigators will submit an average of 50 studies a year.
Currently, the agency estimates the reporting requirements contained in
part 312 (21 CFR 312) to average 123.34 hours per respondent annually.
Reporting requirements are contained in the following sections of part
312: 312.7, 312.10, 312.23, 312.30, 312.31, 312.32, 312.33, 312.35,
312.36, 312.38, 312.41, 312.44(c)(d), 312.45, 312.47, 312.53, 312.55,
312.56, 312.58, 312.64, 312.66, 312.70, 312.83, 312.85, 312.110,
312.120(b), 312.120(c)(3), 312.140, and 312.145. FDA estimates that
respondents will increase by 450 annually, resulting in an increase of
55,503 hours over that currently estimated. The reporting burden for
respondents will, as a result, increase from an estimated 3,926,308
hours annually to 3,971,811 hours annually.
New Sec. 312.54(b) proposes to require the sponsor to provide
information when an IRB determines that it cannot approve the research
because it does not meet the criteria in the exception in Sec. 50.24(a)
or because of other relevant ethical concerns. This information is to
be provided promptly in writing to FDA, investigators who are asked to
participate in the clinical investigation or a substantially equivalent
investigation, and other IRB's that are asked to review the
investigation or a substantially equivalent investigation. In accord
with the Paperwork Reduction Act of 1995, the agency discloses that
this rule requires this third party notification.
For recordkeeping, under Sec. 312.52, 312.57, 312.59, 312.62(a),
312.62(b), 312.62(c), 312.160(a) and (c), the agency estimated that an
average of 165.13 hours were spent per respondent. For the estimated
additional 450 recordkeeping respondents invoking this rule, this would
result in approximately 74,309 hours annually. The recordkeeping burden
for respondents will, as a result, increase from an estimated 2,244,090
hours annually to 2,318,399 hours annually.
For Investigational Devices Exemption Reports and Records under OMB
Control No. 0910-0078, the agency estimates that 35 studies proposing
to invoke this exception will be submitted to the agency annually. The
number of studies upon which the current paperwork reporting burden is
estimated (Sec. 812.20, 812.25, 812.27, 812.35, and 812.150) may,
therefore, increase from 244 original submissions to 279 original
submissions, increasing the number of hours by 2,800 for respondents
(estimated at 80 hours per submission), from a total of 19,520 to
22,320 hours annually.
New Sec. 812.47(b) proposes to require the sponsor to provide
information when an IRB determines that it cannot approve the research
because it does not meet the criteria in the exception in Sec. 50.24(a)
of this chapter or because of other relevant ethical concerns. This
information is to be provided promptly in writing to FDA, investigators
who are asked to participate in the clinical investigation or a
substantially equivalent investigation, and other IRB's that are asked
to review the investigation or a substantially equivalent
investigation. In accord with the Paperwork Reduction Act of 1995, the
agency discloses that this rule requires this third party notification.
The number of recordkeepers, under Secs. 812.43 and 812.140, is
currently estimated at 700; this number is not expected to change. The
estimated number of annual hours for recordkeeping requirements is
expected to increase by 350 hours. The agency had estimated that
original submissions require 10 hours annually of recordkeeping per
submission; recordkeeping related to studies invoking this rule are
expected to increase the submissions from 244 to a total of 279.
As required by section 3507(d) of the Paperwork Reduction Act of
1995, FDA has submitted a copy of this rule to OMB for its review of
these previously approved information collection requirements. The
agency solicited comments on the information collection requirements in
order to: (1) Evaluate whether the collection of information is
necessary for the proper performance of the functions of the agency,
including whether the information will have practical utility; (2)
evaluate the accuracy of the agency's estimate of the burden of the
collection of information, including the validity of the methodology
and assumptions used; (3) enhance the quality, utility, and clarity of
the information to be collected; and (4) minimize the burden of the
collection of information on those who are to respond, including
through the use of appropriate automated, electronic, mechanical, or
other technological collection techniques or other forms of information
technology, e.g., permitting electronic submission of responses.

List of Subjects

21 CFR Part 50

Human research subjects, Prisoners, Reporting and recordkeeping
requirements, Safety.

21 CFR Part 56

Human research subjects, Reporting and recordkeeping requirements,
Safety.

21 CFR Part 312

Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.

[[Page 51528]]

21 CFR Part 314

Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 601

Administrative practice and procedure, Biologics, Confidential
business information.

21 CFR Part 812

Health records, Medical devices, Medical research, Reporting and
recordkeeping requirements.

21 CFR Part 814

Administrative practice and procedure, Confidential business
information, Medical devices, Medical research, Reporting and
recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts
50, 56, 312, 314, 601, 812, and 814 are amended as follows:

PART 50--PROTECTION OF HUMAN SUBJECTS

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

Authority: Secs. 201, 406, 408, 409, 502, 503, 505, 506, 507,
510, 513-516, 518-520, 701, 721, 801 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 321, 346, 346a, 348, 352, 353, 355, 356,
357, 360, 360c-360f, 360h-360j, 371, 379e, 381); secs. 215, 301,
351, 354-360F of the Public Health Service Act (42 U.S.C. 216, 241,
262, 263b-263n).

2. Section 50.3 is amended by adding a new paragraph (n) to read as
follows:

Sec. 50.3 Definitions.

* * * * *
(n) Family member means any one of the following legally competent
persons: Spouse; parents; children (including adopted children);
brothers, sisters, and spouses of brothers and sisters; and any
individual related by blood or affinity whose close association with
the subject is the equivalent of a family relationship.
3. Section 50.24 is added to subpart B to read as follows:

Sec. 50.24 Exception from informed consent requirements for emergency
research.

(a) The IRB responsible for the review, approval, and continuing
review of the clinical investigation described in this section may
approve that investigation without requiring that informed consent of
all research subjects be obtained if the IRB (with the concurrence of a
licensed physician who is a member of or consultant to the IRB and who
is not otherwise participating in the clinical investigation) finds and
documents each of the following:
(1) The human subjects are in a life-threatening situation,
available treatments are unproven or unsatisfactory, and the collection
of valid scientific evidence, which may include evidence obtained
through randomized placebo-controlled investigations, is necessary to
determine the safety and effectiveness of particular interventions.
(2) Obtaining informed consent is not feasible because:
(i) The subjects will not be able to give their informed consent as
a result of their medical condition;
(ii) The intervention under investigation must be administered
before consent from the subjects' legally authorized representatives is
feasible; and
(iii) There is no reasonable way to identify prospectively the
individuals likely to become eligible for participation in the clinical
investigation.
(3) Participation in the research holds out the prospect of direct
benefit to the subjects because:
(i) Subjects are facing a life-threatening situation that
necessitates intervention;
(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; and
(iii) Risks associated with the investigation are reasonable in
relation to what is known about 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 or activity.
(4) The clinical investigation could not practicably be carried out
without the waiver.
(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
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.
(6) The IRB has reviewed and approved informed consent procedures
and an informed consent document consistent with Sec. 50.25. These
procedures and the informed consent document are to be used with
subjects or their legally authorized representatives in situations
where use of such procedures and documents is feasible. The IRB has
reviewed and approved procedures and information to be used when
providing an opportunity for a family member to object to a subject's
participation in the clinical investigation consistent with paragraph
(a)(7)(v) of this section.
(7) Additional protections of the rights and welfare of the
subjects will be provided, including, at least:
(i) Consultation (including, where appropriate, consultation
carried out by the IRB) with representatives of the communities in
which the clinical investigation will be conducted and from which the
subjects will be drawn;
(ii) Public disclosure to the communities in which the clinical
investigation will be conducted and from which the subjects will be
drawn, prior to initiation of the clinical investigation, of plans for
the investigation and its risks and expected benefits;
(iii) Public disclosure of sufficient information following
completion of the clinical investigation to apprise the community and
researchers of the study, including the demographic characteristics of
the research population, and its results;
(iv) Establishment of an independent data monitoring committee to
exercise oversight of the clinical investigation; and
(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.
(b) The IRB is responsible for ensuring that procedures are in
place to inform, at the earliest feasible opportunity, each subject, or
if the subject remains incapacitated, a legally authorized
representative of the subject, or if such a representative is not
reasonably available, a family member, of the subject's inclusion in
the clinical investigation, the details of the

[[Page 51529]]

investigation and other information contained in the informed consent
document. The IRB shall also ensure that there is a procedure to inform
the subject, or if the subject remains incapacitated, a legally
authorized representative of the subject, or if such a representative
is not reasonably available, a family member, that he or she may
discontinue the subject's participation at any time without penalty or
loss of benefits to which the subject is otherwise entitled. If a
legally authorized representative or family member is told about the
clinical investigation and the subject's condition improves, the
subject is also to be informed as soon as feasible. If a subject is
entered into a clinical investigation with waived consent and the
subject dies before a legally authorized representative or family
member can be contacted, information about the clinical investigation
is to be provided to the subject's legally authorized representative or
family member, if feasible.
(c) The IRB determinations required by paragraph (a) of this
section and the documentation required by paragraph (e) of this section
are to be retained by the IRB for at least 3 years after completion of
the clinical investigation, and the records shall be accessible for
inspection and copying by FDA in accordance with Sec. 56.115(b) of this
chapter.
(d) Protocols involving an exception to the informed consent
requirement under this section must be performed under a separate
investigational new drug application (IND) or investigational device
exemption (IDE) that clearly identifies such protocols as protocols
that may include subjects who are unable to consent. The submission of
those protocols in a separate IND/IDE is required even if an IND for
the same drug product or an IDE for the same device already exists.
Applications for investigations under this section may not be submitted
as amendments under Secs. 312.30 or 812.35 of this chapter.
(e) If an IRB determines that it cannot approve a clinical
investigation because the investigation does not meet the criteria in
the exception provided under paragraph (a) of this section or because
of other relevant ethical concerns, the IRB must document its findings
and provide these findings promptly in writing to the clinical
investigator and to the sponsor of the clinical investigation. The
sponsor of the clinical investigation must promptly disclose this
information to FDA and to the sponsor's clinical investigators who are
participating or are asked to participate in this or a substantially
equivalent clinical investigation of the sponsor, and to other IRB's
that have been, or are, asked to review this or a substantially
equivalent investigation by that sponsor.

PART 56--INSTITUTIONAL REVIEW BOARDS

4. The authority citation for 21 CFR part 56 continues to read as
follows:

Authority: Secs. 201, 406, 408, 409, 501, 502, 503, 505, 506,
507, 510, 513-516, 518-520, 701, 721, 801 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 321, 346, 346a, 348, 351, 352, 353, 355,
356, 357, 360, 360c-360f, 360h-360j, 371, 379e, 381); secs. 215,
301, 351, 354-360F of the Public Health Service Act (42 U.S.C 216,
241, 262, 263b-263n).

5. Section 56.109 is amended by revising paragraph (c), by
redesignating paragraphs (d) and (e) as paragraphs (e) and (f), by
adding two new sentences to the end of newly redesignated paragraph
(e), and by adding new paragraphs (d) and (g) to read as follows:

Sec. 56.109 IRB review of research.

* * * * *
(c) An IRB shall require documentation of informed consent in
accordance with Sec. 50.27 of this chapter, except as follows:
(1) The IRB may, for some or all subjects, waive the requirement
that the subject, or the subject's legally authorized representative,
sign a written consent form if it finds that the research presents no
more than minimal risk of harm to subjects and involves no procedures
for which written consent is normally required outside the research
context; or
(2) The IRB may, for some or all subjects, find that the
requirements in Sec. 50.24 of this chapter for an exception from
informed consent for emergency research are met.
(d) In cases where the documentation requirement is waived under
paragraph (c)(1) of this section, the IRB may require the investigator
to provide subjects with a written statement regarding the research.
(e)* * * For investigations involving an exception to informed
consent under Sec. 50.24 of this chapter, an IRB shall promptly notify
in writing the investigator and the sponsor of the research when an IRB
determines that it cannot approve the research because it does not meet
the criteria in the exception provided under Sec. 50.24(a) of this
chapter or because of other relevant ethical concerns. The written
notification shall include a statement of the reasons for the IRB's
determination.
* * * * *
(g) An IRB shall provide in writing to the sponsor of research
involving an exception to informed consent under Sec. 50.24 of this
chapter a copy of information that has been publicly disclosed under
Sec. 50.24(a)(7)(ii) and (a)(7)(iii) of this chapter. The IRB shall
provide this information to the sponsor promptly so that the sponsor is
aware that such disclosure has occurred. Upon receipt, the sponsor
shall provide copies of the information disclosed to FDA.

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

6. The authority citation for 21 CFR part 312 continues to read as
follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C 321, 331, 351,
352, 353, 355, 356, 357, 371); sec 351 of the Public Health Service
Act (42 U.S.C. 262).

7. Section 312.2 is amended by adding paragraph (b)(6) to read as
follows:

Sec. 312.2 Applicability.

* * * * *
(b) * * *
(6) A clinical investigation involving an exception from informed
consent under Sec. 50.24 of this chapter is not exempt from the
requirements of this part.
* * * * *
8. Section 312.20 is amended by adding new paragraph (c) to read as
follows:

Sec. 312.20 Requirement for an IND.

* * * * *
(c) A sponsor shall submit a separate IND for any clinical
investigation involving an exception from informed consent under
Sec. 50.24 of this chapter. Such a clinical investigation is not
permitted to proceed without the prior written authorization from FDA.
FDA shall provide such written authorization 30 days after FDA receives
the IND or earlier.
9. Section 312.23 is amended by adding new paragraph (f) to read as
follows:

Sec. 312.23 IND content and format.

* * * * *
(f) Identification of exception from informed consent. If the
investigation involves an exception from informed consent under
Sec. 50.24 of this chapter, the sponsor shall prominently identify on
the cover sheet that the investigation is subject to the requirements
in Sec. 50.24 of this chapter.
10. Section 312.30 is amended by adding a new sentence to the end
of the introductory text to read as follows:

[[Page 51530]]

Sec. 312.30 Protocol amendments.

* * * Whenever a sponsor intends to conduct a clinical
investigation with an exception from informed consent for emergency
research as set forth in Sec. 50.24 of this chapter, the sponsor shall
submit a separate IND for such investigation.
* * * * *
11. Section 312.42 is amended by adding new paragraph (b)(5) to
read as follows:

Sec. 312.42 Clinical holds and requests for modification.

* * * * *
(b) * * *
(5) Clinical hold of any investigation involving an exception from
informed consent under Sec. 50.24 of this chapter. FDA may place a
proposed or ongoing investigation involving an exception from informed
consent under Sec. 50.24 of this chapter on clinical hold if it is
determined that:
(i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this
section apply; or
(ii) The pertinent criteria in Sec. 50.24 of this chapter for such
an investigation to begin or continue are not submitted or not
satisfied.
* * * * *
12. New section 312.54 is added to subpart D to read as follows:

Sec. 312.54 Emergency research under Sec. 50.24 of this chapter.

(a) The sponsor shall monitor the progress of all investigations
involving an exception from informed consent under Sec. 50.24 of this
chapter. When the sponsor receives from the IRB information concerning
the public disclosures required by Sec. 50.24(a)(7)(ii) and (a)(7)(iii)
of this chapter, the sponsor promptly shall submit to the IND file and
to Docket Number 95S-0158 in the Dockets Management Branch (HFA-305),
Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville,
MD 20857, copies of the information that was disclosed, identified by
the IND number.
(b) The sponsor also shall monitor such investigations to identify
when an IRB determines that it cannot approve the research because it
does not meet the criteria in the exception in Sec. 50.24(a) of this
chapter or because of other relevant ethical concerns. The sponsor
promptly shall provide this information in writing to FDA,
investigators who are asked to participate in this or a substantially
equivalent clinical investigation, and other IRB's that are asked to
review this or a substantially equivalent investigation.
13. Section 312.60 is amended by revising the second and third
sentences in the text as follows:

Sec. 312.60 General responsibilities of investigators.

* * * An investigator shall, in accordance with the provisions of
part 50 of this chapter, obtain the informed consent of each human
subject to whom the drug is administered, except as provided in
Secs. 50.23 or 50.24 of this chapter. Additional specific
responsibilities of clinical investigators are set forth in this part
and in parts 50 and 56 of this chapter.
14. Section 312.130 is amended by adding a new paragraph (d) to
read as follows:

Sec. 312.130 Availability for public disclosure of data and
information in an IND.

* * * * *
(d) The availability of information required to be publicly
disclosed for investigations involving an exception from informed
consent under Sec. 50.24 of this chapter will be handled as follows:
Persons wishing to request the publicly disclosable information in the
IND that was required to be filed in Docket Number 95S-0158 in the
Dockets Management Branch (HFA-305), Food and Drug Administration,
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, shall submit a
request under the Freedom of Information Act.

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN
ANTIBIOTIC DRUG

15. The authority citation for 21 CFR part 314 continues to read as
follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701,
704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321,
331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).

16. Section 314.430 is amended by redesignating paragraph (d) as
paragraph (d)(1) and by adding new paragraph (d)(2) to read as follows:

Sec. 314.430 Availability for public disclosure of data and
information in an application or abbreviated application.

* * * * *
(d)(1) * * *
(2) Notwithstanding paragraph (d)(1) of this section, FDA will make
available to the public upon request the information in the
investigational new drug application that was required to be filed in
Docket Number 95S-0158 in the Dockets Management Branch (HFA-305), Food
and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD
20857, for investigations involving an exception from informed consent
under Sec. 50.24 of this chapter. Persons wishing to request this
information shall submit a request under the Freedom of Information
Act.
* * * * *

PART 601--LICENSING

17. The authority citation for 21 CFR part 601 continues to read as
follows:

Authority: Secs. 201, 501, 502, 503, 505, 510, 513-516, 518-520,
701, 704, 721, 801 of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 374,
379e, 381); secs. 215, 301, 351, 352 of the Public Health Service
Act (42 U.S.C. 216, 241, 262, 263); secs. 2-12 of the Fair Packaging
and Labeling Act (15 U.S.C. 1451-1461).

18. Section 601.51 is amended by redesignating paragraph (d) as
paragraph (d)(1) and by adding new paragraph (d)(2) to read as follows:

Sec. 601.51 Confidentiality of data and information in applications
for establishment and product licenses.

* * * * *
(d)(1) * * *
(2) Notwithstanding paragraph (d)(1) of this section, FDA will make
available to the public upon request the information in the IND that
was required to be filed in Docket Number 95S-0158 in the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857, for investigations
involving an exception from informed consent under Sec. 50.24 of this
chapter. Persons wishing to request this information shall submit a
request under the Freedom of Information Act.
* * * * *

PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS

19. The authority citation for 21 CFR part 812 continues to read as
follows:

Authority: Secs. 301, 501, 502, 503, 505, 506, 507, 510, 513-
516, 518-520, 701, 702, 704, 721, 801 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 331, 351, 352, 353, 355, 356, 357, 360,
360c-360f, 360h-360j, 371, 372, 374, 379e, 381); secs. 215, 301,
351, 354-360F of the Public Health Service Act (42 U.S.C 216, 241,
262, 263b-263n).

20. Section 812.20 is amended by revising paragraph (a)(1) and
adding new paragraph (a)(4) to read as follows:

Sec. 812.20 Application.

(a) Submission. (1) A sponsor shall submit an application to FDA if
the sponsor intends to use a significant risk device in an
investigation, intends to conduct an investigation that involves an
exception from informed consent under Sec. 50.24 of this chapter, or if
FDA

[[Page 51531]]

notifies the sponsor that an application is required for an
investigation.
* * * * *
(4)(i) A sponsor shall submit a separate IDE for any clinical
investigation involving an exception from informed consent under
Sec. 50.24 of this chapter. Such a clinical investigation is not
permitted to proceed without the prior written authorization of FDA.
FDA shall provide such written authorization 30 days after FDA receives
the IDE or earlier.
(ii) If the investigation involves an exception from informed
consent under Sec. 50.24 of this chapter, the sponsor shall prominently
identify on the cover sheet that the investigation is subject to the
requirements in Sec. 50.24 of this chapter.
* * * * *
20. Section 812.35 is amended by adding a new sentence to the end
of paragraph (a) to read as follows:

Sec. 812.35 Supplemental applications.

(a) * * * Whenever a sponsor intends to conduct a clinical
investigation with an exception from informed consent for emergency
research as set forth in Sec. 50.24 of this chapter, the sponsor shall
submit a separate IDE for such investigation.
* * * * *
21. Section 812.38 is amended by adding a new paragraph (b)(4) to
read as follows:

Sec. 812.38 Confidentiality of data and information.

* * * * *
(b) * * *
(4) Notwithstanding paragraph (b)(2) of this section, FDA will make
available to the public, upon request, the information in the IDE that
was required to be filed in Docket Number 95S-0158 in the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857, for investigations
involving an exception from informed consent under Sec. 50.24 of this
chapter. Persons wishing to request this information shall submit a
request under the Freedom of Information Act.
* * * * *
22. New section 812.47 is added to subpart C to read as follows:

Sec. 812.47 Emergency research under Sec. 50.24 of this chapter.

(a) The sponsor shall monitor the progress of all investigations
involving an exception from informed consent under Sec. 50.24 of this
chapter. When the sponsor receives from the IRB information concerning
the public disclosures under Sec. 50.24(a)(7)(ii) and (a)(7)(iii) of
this chapter, the sponsor shall promptly submit to the IDE file and to
Docket Number 95S-0158 in the Dockets Management Branch (HFA-305), Food
and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD
20857, copies of the information that was disclosed, identified by the
IDE number.
(b) The sponsor also shall monitor such investigations to determine
when an IRB determines that it cannot approve the research because it
does not meet the criteria in the exception in Sec. 50.24(a) of this
chapter or because of other relevant ethical concerns. The sponsor
promptly shall provide this information in writing to FDA investigators
who are asked to participate in this or a substantially equivalent
clinical investigation and other IRB's that are asked to review this or
a substantially equivalent investigation.

PART 814--PREMARKET APPROVAL OF MEDICAL DEVICES

23. The authority citation for 21 CFR part 814 is revised to read
as follows:

Authority: Secs. 501, 502, 503, 510, 513-520, 701, 702, 703,
704, 705, 708, 721, 801 of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 351, 352, 353, 360, 360c-360j, 371, 372, 373, 374, 375,
379, 379e, 381).

24. Section 814.9 is amended by redesignating paragraph (d) as
paragraph (d)(1) and by adding new paragraph (d)(2) to read as follows

Sec. 814.9 Confidentiality of data and information in a premarket
application (PMA) file.

* * * * *
(d)(1) * * *
(2) Notwithstanding paragraph (d)(1) of this section, FDA will make
available to the public upon request the information in the IDE that
was required to be filed in Docket Number 95S-0158 in the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857, for investigations
involving an exception from informed consent under Sec. 50.24 of this
chapter. Persons wishing to request this information shall submit a
request under the Freedom of Information Act.
* * * * *

Dated: July 17, 1996.
David A. Kessler,
Commissioner of Food and Drugs.

Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 96-24967 Filed 9-26-96; 8:59 am]
BILLING CODE 4160-01-F