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.

-----------------------------------------------------------------------

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

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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