[Federal Register Volume 60, Number 183 (Thursday, September 21, 1995)]
[Proposed Rules]
[Pages 49086-49103]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-23239]




[[Page 49085]]

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Part III





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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21 CFR Part 50, et al.



Protection of Human Subjects; Informed Consent; Proposed Rule

  Federal Register / Vol. 60, No 183 / Thursday, September 21, 1995 / 
Proposed Rules  

[[Page 49086]]


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: Proposed rule; opportunity for public comment.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
its current informed consent regulations to permit harmonization of 
Federal policies on emergency research, and to reduce confusion as to 
when such research can proceed without obtaining informed consent. The 
regulation provides a narrow exception to the requirement for obtaining 
and documenting informed consent from each human subject prior to 
initiation of an experimental treatment. The exception would apply to a 
limited class of research activities involving human subjects who, 
because of their life-threatening medical condition and the 
unavailability of legally authorized persons to represent them, are in 
need of emergency medical intervention and cannot provide legally 
effective informed consent. FDA is proposing 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.

DATES: Written comments by November 6, 1995.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., 
Rockville, MD 20857.

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. Harmonization

    Recently, the Department of Health and Human Services (HHS) 
authorized Institutional Review Boards (IRB's) to waive informed 
consent requirements for one specific National Institutes of Health-
funded project under strictly defined circumstances similar to those 
authorized by these FDA proposed rules. (See HHS Notice of Action 
Related to Emergency Research Activity at 60 FR 38353 through 38354, 
July 26, 1995.) HHS is considering a general IRB authorization to waive 
informed consent requirements under the same strictly defined 
circumstances as those identified in the specific project waiver 
authorization and in the FDA proposed rule. Any HHS decision to grant a 
general informed consent waiver authority to IRB's for emergency 
research activities will be made with attention to harmonization with 
action on these FDA proposed rules and will be published in the Federal 
Register. It is the intent of HHS to bring the HHS (45 CFR part 46) and 
FDA (21 CFR part 50) regulations into harmony on this matter at the 
time this rule is made final.

II. Informed Consent Regulations

    Much of what has become standard, accepted, medical therapies for 
use in acute or resuscitation clinical care has not been evaluated by 
adequate trials that demonstrate either safety or effectiveness. 
Controlled clinical trials have demonstrated that some therapies that 
have become standard medical practice are ineffective or even harmful. 
Other standard therapies, although shown to be effective in clinical 
trials, have significant limitations, in that, for example, they only 
work in a small percentage of those individuals who receive the 
therapies, so that testing of improved or additional therapies remains 
critically important. By permitting certain adequate and well-
controlled clinical trials to occur that involve human subjects who are 
confronted by a life-threatening condition and who also are unable to 
give informed consent because of that 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.
    Sections 505(i), 507(d), and 520(g) of the Federal Food, Drug, and 
Cosmetic Act (the act) (21 U.S.C. 355(i), 357(d), and 360j(g)) require 
FDA to publish regulations governing the use in humans of drugs, 
including certain biologics and antibiotics, and devices in clinical 
investigations (hereafter ``investigational drugs'' and 
``investigational devices,'' respectively).
    In 1962, amendments to the act (Section 505(d)) provided that drugs 
could be approved for marketing only if they were found, on the basis 
of adequate and well-controlled clinical investigations, to be 
effective as well as safe for their intended use. Section 505(i) of the 
act also provided that unapproved drugs could be made available to 
humans for investigational use only. Section 505(i) of the act further 
provided for the issuance of regulations which condition the 
investigational use, in part, on:
    * * * the manufacturer * * * requiring that experts using such 
drugs * * * certify * * * that they will inform any human beings to 
whom such drugs, or any controls used in connection therewith, are 
being administered, or their representatives, that such drugs are 
being used for investigational purposes and will obtain the consent 
of such human beings or their representatives, except where they 
deem it not feasible, or in their professional judgment, contrary to 
the best interests of such human beings.-
This provision created the general requirement of informed consent for 
investigations conducted under sections 505(i) and 507(d) of the act.
    The Medical Device Amendments of 1976 revised FDA's authority to 
regulate medical devices and, in part, set up a statutory scheme under 
which devices would be classified and subjected to varying degrees of 
regulatory control according to classification. Section 520(g) of the 
act created a system under which the safety and effectiveness of new 
medical devices could be investigated by qualified experts. Among other 
requirements, section 520(g)(3)(D) of the act provided that the sponsor 
of clinical investigations must:
    * * * assure that informed consent will be obtained from each 
human subject (or his representative) * * * except where subject to 
such conditions as the Secretary may prescribe, the investigator 
conducting or supervising the proposed clinical testing of the 
device determines in writing that there exists a life threatening 
situation involving the human subject of such testing which 
necessitates the use of such device and it is not feasible to obtain 
informed consent from the subject and there is not sufficient time 
to obtain such consent from his representative.
Section 520(g)(3)(D) of the act further provided that this 
determination:
    * * * shall be concurred in by a licensed physician who is not 
involved in the testing of the human subject with respect to which 
such determination is made unless immediate use of the device is 
required to save the life of the human subject of such testing and 
there is not sufficient time to obtain such concurrence.
    Sections 505(i) and 507(d) of the act permit waiver of informed 
consent either when ``it [is] not feasible'' or when it is ``contrary 
to the best interests of such [subjects].'' Section 520(g) of the act 
permits waiver of informed consent in life-threatening situations which 
``necessitates the use of such device and it is not feasible to obtain 
informed consent * * *.''

[[Page 49087]]

    In 1979, following the enactment of the Medical Device Amendments, 
FDA proposed rules revising its regulations governing informed consent 
(44 FR 47713, August 14, 1979). FDA issued final regulations governing 
informed consent in the Federal Register of January 27, 1981 (46 FR 
8942). Those regulations, codified in part 50 (21 CFR part 50), apply 
to any clinical investigation subject to regulation by FDA under 
sections 505(i), 507(d), and 520(g) of the act, as well as to clinical 
investigations that support applications for research or marketing 
permits for products regulated by FDA. The agency explained its reasons 
for revising its regulations governing informed consent in the preamble 
to these final regulations. These reasons included, among others: (1) 
The desire to address the informed consent provision included in the 
device amendments; (2) the need to create a uniform set of agency-wide 
informed consent standards for more effective administration of the 
agency's bioresearch monitoring program; (3) implementation of 
recommendations of the National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research; and (4) harmonization 
of FDA rules with those of the HHS.
    Some comments on the proposed regulations questioned whether the 
regulations met the statutory requirements of sections 505, 507, and 
520 of the act, but all comments approved of the elimination of 
regulatory confusion and the enhancement of human subject protections. 
In responding to public comments, the agency stated its belief that the 
standard regarding informed consent expressed in the 1962 Drug 
Amendments was the standard of its time, but that it was no longer the 
current standard of practice, given progress in the understanding of 
ethical principles and their relevance to biomedical research. The 
preamble went on to express the agency's intent to adopt a single 
standard that reflected both the most current congressional thinking on 
informed consent and the important ethical principles and social 
policies underlying the doctrine of consent. (See 46 FR 8942 to 8944, 
January 27, 1981.) In the preamble to the August 14, 1979, proposed 
rule, FDA further explained the requirement that a determination be 
made as to lack of an available alternative method of therapy that may 
save the life of the subject. FDA stated that this requirement:
    * * * has been added to prevent routine reliance on the 
exception. This additional requirement should provide guidance to 
investigators regarding those exceptional situations in which 
informed consent need not be obtained. As noted above, obtaining 
informed consent has come to be a standard of practice for 
professional clinical investigators. Defining those circumstances 
when informed consent need not be obtained should provide a clearer 
understanding of how to determine when informed consent is ``not 
feasible.''
(44 FR 47713 at 47720).
    In Sec. 50.23(a)) of the 1981 rule, FDA required informed consent 
except when obtaining informed consent is determined not to be feasible 
for the emergency use of an investigational article, where:
    * * * both the investigator and a physician who is not otherwise 
participating in the clinical investigation certify in writing all 
of the following: (1) The human subject is confronted by a life-
threatening situation necessitating the use of the test article. (2) 
Informed consent cannot be obtained from the subject because of an 
inability to communicate with, or obtain legally effective consent 
from, the subject. (3) Time is not sufficient to obtain consent from 
the subject's legal representative. (4) 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.
If immediate use of the investigational product is, in the 
investigator's opinion, required to preserve the life of the subject, 
and there is not sufficient time to obtain an independent physician's 
determination in advance of using the product, the use of the product 
is to be reviewed and evaluated in writing by a physician who is not 
participating in the study within 5 working days after its use (46 FR 
8951, January 27, 1981).
    On December 21, 1990, FDA published an interim rule in the Federal 
Register (55 FR 52814), amending these informed consent regulations to 
permit an exception from the general requirements for informed consent 
in certain military combat circumstances. As codified in Sec. 50.23(d), 
the Commissioner of Food and Drugs (the Commissioner) is permitted to 
make a determination that obtaining informed consent from military 
personnel for the use of an investigational drug or biologic is not 
feasible in certain battlefield or combat-related situations. The 
Commissioner is authorized to make such a determination when the 
physician(s) responsible for the medical care of the military personnel 
involved and the investigator(s) named in the investigational new drug 
application (IND) provide written justification for their conclusions 
that, in the use of specific investigational drugs or biologics in a 
specific combat-related situation, obtaining informed consent is not 
feasible and withholding treatment would be contrary to the best 
interests of the military personnel because of military combat 
exigencies and that the waiver of informed consent is ethically 
justified (52 FR 52814, December 21, 1990). This exception was upheld 
in the United States Court of Appeals for the D.C. Circuit in 1991. 
(See Doe v. Sullivan, 938 F.2d 1370 (D.C. Cir. 1991), affirming 756 F. 
Supp. 12 (D. D.C. 1991)).
    In June 1991, the Office of Science and Technology Policy published 
the common Federal Policy for the Protection of Human Subjects (common 
rule) in the Federal Register. (56 FR 28002, June 18, 1991.) Issuance 
of the common rule was the result of more than a decade of work by 
Federal agencies and departments that conduct, support, or regulate 
research involving human subjects. The common rule implemented a 
recommendation of the President's Commission for the Study of Ethical 
Problems in Medicine and Biomedical and Behavioral Research 
(President's Commission). This recommendation was included in the 
December 1981 report of the President's Commission, entitled, ``First 
Biennial Report on the Adequacy and Uniformity of Federal Rules and 
Policies, and their Implementation, for the Protection of Human 
Subjects in Biomedical and Behavioral Research, Protecting Human 
Subjects,'' which stated:
    The President should, through appropriate action, require that 
all federal departments and agencies adopt as a common core the 
regulations governing research with human subjects issued by the 
Department of Health and Human Services (codified at 45 CFR 46), as 
periodically amended or revised, while permitting additions needed 
by any department or agency that are not inconsistent with these 
core provisions.
(56 FR 28004, June 18, 1991)
    In May 1982, the Chairman of the Federal Coordinating Council for 
Science, Engineering, and Technology appointed an Ad Hoc Committee for 
the Protection of Human Subjects. The Ad Hoc Committee agreed that 
uniformity was desirable among departments and agencies and worked to 
develop a model Federal policy, which became the common rule, to 
``eliminate unnecessary regulation and to promote increased 
understanding and ease of compliance by institutions that conduct 
federally supported or regulated research involving human subjects.'' 
(56 FR 28004, June 18, 1991.) Section xx.116(d) of the common rule 
described the conditions under which an Institutional Review Board 
(IRB) was authorized to waive some or all of the elements of informed 
consent. This section was adopted unchanged into the HHS regulations 
(45 CFR part 46). (56 FR 

[[Page 49088]]
28022, June 18, 1991.) The HHS regulations apply to research supported 
or conducted by HHS; they are implemented under the direction of the 
Office for Protection from Research Risks (OPRR) at the National 
Institutes of Health (NIH).
    Although FDA concurred in the common rule and amended its 
regulations in 21 CFR parts 50 and 56 to conform them to the common 
rule to the extent permitted by the act, FDA regulations diverged from 
section xx.116(d). (56 FR 28025, June 18, 1991.) In describing the 
reason for this divergence, FDA stated as follows:
    The act requires that informed consent be obtained from all 
subjects of clinical investigations except in very limited 
circumstances (see, e.g., 21 U.S.C. 355(i), 357(d)(3), and 
360j(g)(3)(D), which establish requirements for the conduct of 
clinical investigations for drugs, antibiotic drugs, and medical 
devices, respectively). FDA does not have the authority under the 
act to waive this requirement.
    (53 FR 45679, November 10, 1988).
    Thus, FDA retained its exception language dealing with individual 
emergency use which was contained in FDA's 1981 regulations 
(Sec. 50.23(a) through (c)); this exception remains applicable today. 
FDA modified other aspects of parts 50 and 56 (21 CFR part 56) in the 
Federal Register on June 18, 1991, in order to bring them into harmony 
with the common rule (56 FR 28025).
    IRB's that are subject to both the HHS and FDA regulations have had 
to ensure that both the criteria in the common rule as set forth at 45 
CFR part 46 and in FDA's regulation at 21 CFR part 50 are met in order 
to permit research to be approved.
    On many occasions IRB's, functioning under HHS regulations, have 
been unable to approve research that required use of the waiver allowed 
by 45 CFR 46.116(d) because the risk involved in emergency research 
activities was thought to be greater than minimal and therefore the 
condition that the research activity ``involve no more than minimal 
risk'' could not be met. (See 45 CFR 46.116(d).)
    Similarly, FDA has permitted only a very limited number of 
controlled trials involving investigational drugs to be conducted 
without informed consent under its current exception provisions. This 
is because Sec. 50.23(a) permits the use of an investigational product 
without consent only in order to save the life of a patient, and if 
there is no other approved or generally recognized alternative therapy 
available that provides an equal or greater likelihood of saving the 
life of the patient. In other words, the investigator and the 
independent physician have had to determine that the investigational 
product represented the best available treatment for the patient.
    The agency has permitted limited trials involving investigational 
drugs to be conducted by interpreting Sec. 50.23(a) as describing the 
general state of circumstances that must exist as a threshold to 
determining that informed consent is not feasible (Refs. 1 and 2). The 
term ``human subject,'' defined in Sec. 50.3(g) as one who participates 
in research either as a recipient of the test article or as a control, 
supports the interpretation that this provision was intended to be used 
in the setting of an investigation conducted in accordance with 
principles of good clinical design, including blinding, randomization, 
and, where appropriate, use of a placebo as a control.

III. Background on Current Practices in the Research Community

    Most therapeutic intervention in acute care and emergency research 
must be initiated immediately to be life-saving. For victims of heart 
attacks or head injuries, for example, this intervention often must be 
instituted in the field, prior to hospital admission, when the 
individual is usually found to be unresponsive and unable to 
communicate and where there usually is no authorized representative of 
the subject available to give surrogate consent.
    In 1993, the agency became aware that certain IRB's were approving 
research involving interventions in acutely life-threatening situations 
by invoking a ``deferred consent'' procedure. This term was used to 
describe a procedure whereby subjects or representatives of subjects 
are informed, after the fact, that the subject participated, 
unknowingly, in a clinical investigation of an experimental product, 
and was administered a test article in the course of the investigation. 
Subjects or their representatives were then asked to ratify that 
participation retroactively, and to agree to continuing participation 
(Refs. 3 through 6). As described, ``deferred consent'' is nothing 
other than post-hoc ratification. Post-hoc 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 (Ref. 7).
    In August 1993, IRB chairs at institutions with written assurances 
of compliance with HHS regulations were sent a letter by NIH's OPRR 
reiterating the mandate for obtaining legally effective informed 
consent prospectively and reminding them that the only deviation 
allowed by the HHS regulations is contained in 45 CFR 46.116(d), its 
waiver provision. The letter indicated that ``deferred consent'' or 
``ratification'' fails to constitute informed consent under the HHS 
regulations (Ref. 8).
    During the summer of 1993, the Commissioner of Food and Drugs 
received a number of letters from the neurology and emergency medicine 
communities, including the Society for Academic Emergency Medicine, the 
National Coalition for Research in Neurological Disorders, and the 
National Head Injury Foundation, expressing concern about their 
continued ability to conduct placebo controlled research in subjects 
unable to provide informed consent if FDA did not permit ``implied'' or 
``deferred consent.'' The Commissioner responded to these letters on 
September 14, 1993, indicating that FDA did not agree that ``deferred'' 
consent constituted true consent; he stated further that:
    While we recognize that it is not always possible to obtain 
informed consent from subjects prior to the administration of an 
investigational drug, we believe that it is critical to define and 
seek some consensus on how, precisely, patients who cannot give 
consent can be enrolled in such trials * * *. Before establishing 
new policy in this area, the Agency believes that it needs broad 
public and scientific input in order to determine how to balance the 
need for well-controlled studies with the protection of subjects' 
rights. Therefore, we are in the early stages of planning a workshop 
that will be co-sponsored by NIH to obtain necessary advice on this 
topic. * * * *
(Refs. 9 through 12)
    Thus, although the research community is now aware that ``deferred 
consent'' does not meet the requirements of either HHS or FDA rules, 
and does not constitute valid informed consent, it has been given no 
alternative procedure, under which it may conduct emergency research 
under the FDA and HHS regulations, other than the limited exceptions 
and exemptions described previously.

IV. Patients and Research Community's Support for Change in 
Regulation and Congressional Interest

    In correspondence, at meetings, and in published articles, the IRB 
and research communities have expressed their frustration at the 
difficulties they faced in interpreting existing regulations to fit the 
needs of emergency research. They have identified the need for FDA and 
NIH to reach a decision concerning the conduct of these studies that 
would result in a harmonization of the FDA and HHS regulations. Patient 
advocacy 

[[Page 49089]]
groups and researchers have stressed that the research at stake is of 
great importance to patients and the health of the nation and care must 
be taken to ensure that the agencies' regulations do not 
inappropriately disrupt access to, or prevent the development of, 
potentially life-saving treatments for serious illnesses and injuries 
(Refs. 13 through 20). The IRB and research communities have stressed 
that a common position adopted by both FDA and NIH will help eliminate 
confusion concerning which regulations, FDA or HHS or both, need to be 
followed and will eliminate conflicting requirements that must be met 
in order for the research to proceed. This is especially true in cases 
where a majority of the study sites are subject to both sets of 
regulations. Finally, they have argued that it is appropriate that FDA 
and NIH agree on the basic conditions and the ethical conduct of acute 
care research in order to carry out PHS's dual leadership 
responsibility to promote sound biomedical research while helping to 
protect the rights and welfare of human subjects (Refs. 21 through 25).
    The research addressed by this proposed regulation is believed to 
constitute a small fraction of all clinical research. This is because, 
in some instances, an individual may be unconscious or incompetent to 
give informed consent, but immediate involvement in research is not 
needed to promote healing or to prevent death. In those instances, it 
may be possible to delay participation in research until consent from a 
legally authorized representative can be obtained. There are also 
medical conditions that predictably occur in given identifiable patient 
populations. In such cases, prior informed consent can be obtained from 
potential future subjects before the intervention occurs because the 
patient will understand the likelihood of the future need to 
participate in research when consent cannot be obtained. In other 
cases, such as events that occur regularly in already hospitalized, 
acutely ill patients, the majority of subjects will have a legally 
authorized representative readily available to provide surrogate 
consent. In these instances, the research may, in accord with the 
provisions of the law of the jurisdiction, proceed without invoking a 
waiver of informed consent. In those cases that remain, research can 
only be conducted in the absence of informed consent.
    A May 23, 1994, hearing of the Subcommittee on Regulation, Business 
Opportunities, and Technology, House Committee on Small Business, then 
chaired by Representative Ron Wyden, addressed problems encountered in 
securing informed consent of subjects in clinical trials of 
investigational drugs and medical devices (Ref. 26). In Representative 
Wyden's opening remarks, he acknowledged that while informed consent is 
an essential component of biomedical research, there are certain 
conditions under which obtaining informed consent in the classic sense 
may not be possible, and it is imperative that testing of potentially 
life-saving therapies go forward. He further asserted that 
contradictory and confusing Federal policies on informed consent have 
fostered inconsistent application of the Federal requirements on the 
part of investigators and IRB members. Representative Larry Combest, in 
his opening statement, expressed his desire for HHS Secretary Donna 
Shalala to establish consistent Federal rules related to obtaining 
informed consent during research on unapproved drugs and medical 
devices. He emphasized the need to harmonize HHS and FDA regulations 
while streamlining the approval process.
    Researchers, IRB members, device and drug manufacturers, and 
ethicists testified about the state of emergency research and the 
negative impact current regulations have had on the ability of such 
research to proceed; the ethical issues surrounding the conduct of 
emergency research in situations where human subjects are not competent 
to give informed consent; and the need for better guidance from Federal 
agencies. Representatives from NIH and FDA testifying at the hearing 
acknowledged the need to further examine the issue of circumstances 
under which research activities may go forward when informed consent 
cannot be obtained.
    On October 25, 1994, persons associated with several professional 
organizations, institutions, patient advocacy groups, and the bioethics 
community met at the Coalition Conference of Acute Resuscitation and 
Critical Care Researchers (the Coalition) to discuss the current 
Federal regulations regarding informed consent for participation in 
research. Observers from the legal community, congressional and senate 
offices, FDA, and the NIH's OPRR also attended.
    The Coalition conference was convened under the joint sponsorship 
of the American Heart Association and the Society for Academic 
Emergency Medicine and included representatives from the American 
Academy of Clinical Toxicology, the American Association for the 
Surgery of Trauma, the American College of Cardiology, the American 
College of Emergency Physicians, the Applied Research Ethics National 
Association, the Emergency Nurses Association, the Joint Section on 
Neurotrauma and Critical Care, the National Head Injury Foundation, and 
the Society of Critical Care Medicine.
    Following this Coalition conference, the Coalition developed a 
consensus document to offer recommendations to help resolve some of the 
issues concerning informed consent and waiver of consent in emergency 
research. The American Heart Association and the Society for Academic 
Emergency Medicine submitted the consensus statement to FDA. The 
consensus document has been endorsed by a number of professional 
organizations, including the American Academy of Clinical Toxicology, 
the American Academy of Pediatrics' Pediatric Emergency Medicine 
Collaborative Research Committee and Section on Emergency Medicine, the 
American Association for the Surgery of Trauma, the American Autoimmune 
Related Diseases Association, the American Brain Injury Consortium, the 
American College of Emergency Physicians, the Applied Research Ethics 
National Association, the Emergency Nurses Association, the Medical 
Device Manufacturers Association, the National Head Injury Foundation, 
the New England Biomedical Research Coalition, the Society for 
Pediatric Emergency Medicine, the Society for Critical Care Medicine, 
and the National Association of EMS Physicians.
    The consensus document described the importance of emergency 
research, provided background on the current regulations that govern 
waiver of consent in clinical research trials, and reviewed current 
issues arising from the use of waiver of consent in emergency research. 
The consensus document concluded that there are circumstances under 
which it is not feasible to obtain consent for enrollment into a 
protocol involving emergency research; and that, in these 
circumstances, patients are vulnerable both to risks associated with 
research, but also to being denied benefits offered by research 
interventions when no effective standard treatment is known. The 
consensus document contained recommendations ``which should be met when 
the critical nature of the illness or injury, or the need for rapid 
treatment intervention, precludes prospective consent for participation 
in emergency research'' (Ref. 22).
    On January 9 and 10, 1995, FDA and NIH cosponsored a Public Forum 
on Informed Consent in Clinical Research Conducted in Emergency 

[[Page 49090]]
Circumstances, as was proposed by the Commissioner of Food and Drugs in 
his letters of September 14, 1993 (Refs. 9 through 12 and Refs. 23 and 
24). The Coalition consensus document was presented and discussed as 
well as other models for changing the regulatory paradigm (Ref. 25). 
Participants at that public forum affirmed the need to protect research 
subjects while allowing clinical research to proceed if the research 
subjects are in a life-threatening situation, available treatments are 
unproven or unsatisfactory, and immediate intervention is necessary if 
the intervention is to be of benefit (Refs. 25 and 26). Many 
participants expressed concern that the current regulations value 
individual autonomy and the right to informed consent at the expense of 
the principles of beneficence and justice. They argued that when the 
expected outcome of standard therapy is poor, and a promising research 
intervention is available, the principle of beneficence should be 
permitted to take precedence over the principle of autonomy (Ref. 23). 
A minority view expressed was that one cannot ethically assume that 
acutely ill, incompetent patients would, if they were able, choose to 
participate in a research protocol. Those supporting this view believed 
that to exclude these patients from a research protocol did not 
discriminate against them, but rather respected their autonomy (Refs. 
24, 27, and 28).
    Forum participants discussed the ethical, regulatory, and 
operational challenges faced by IRB's and by emergency and acute care 
researchers, as well as ideas for resolving those dilemmas in an 
ethical way. Speakers emphasized that the ``golden hour'' or the 
``window of opportunity'' following acute injury is a concept on which 
modern trauma care is based. ``Nearly all patients who die from injury 
in the first 24 hours do so from processes set in motion at the time of 
injury. Any therapeutic intervention must [therefore] be begun 
immediately to interrupt the injury-induced cascade of body reactions 
leading to death. That is, intervention must be instituted in the field 
by the first response team of paramedics, in the trauma room in the 
operating room, and in the surgical critical care unit'' (Ref. 23, p. 
277).
    Participants agreed that current resuscitation modalities are only 
minimally effective in saving lives and improving outcome and quality 
of life. Trauma and acute care physicians reported frustration in 
employing time-honored treatments that provide little benefit to their 
patients. Many expressed concern that, because of the current Federal 
regulations, emergency care professionals are hesitant to conduct 
appropriately designed clinical trials which are needed to validate or 
discredit current or innovative treatments. During the Public Forum, 
participants provided numerous examples of the chilling effect that the 
current regulations have had on the conduct of clinical research, 
including cardiopulmonary resuscitation (CPR) studies, and studies of 
acute trauma, overdose, acute asthma exacerbations, cardiac arrest, 
head injury, seizures, and stroke (Refs. 23, 24, and 25).-
    Representative of the studies discussed was one in the area of 
sudden cardiac arrest. Each year, approximately 350,000 people in the 
United States suffer a sudden cardiac arrest. Most die, while many 
others are irreversibly harmed by complications such as brain damage. 
In the cases of patients who survive, the risk of recurrence is high 
and the protection offered by easily implantable cardioverter-
defibrillators exemplifies the important successes that can be 
achieved. One of the most critical challenges is to find ways to 
improve the initial survival rate of individuals who are typically 
unresponsive and unable to communicate. Currently, despite efforts to 
instill basic life support education (i.e., standard CPR techniques), 
only a small percentage of individuals who suffer sudden out-of-
hospital cardiac arrests are resuscitated by bystanders. Few survive to 
leave the hospital. This percentage may be as low as 1 to 3 percent in 
some large metropolitan areas, with the best results estimated to be 
only in the 25 percent range. Given the large number of sudden cardiac 
arrests annually in the United States alone, even small improvements in 
care offer enormous life-saving potential (Ref. 29).
    Standard CPR methodology was largely developed on a mechanistic and 
theoretical basis. Improvement or rigorous challenge of the methodology 
is complicated by the difficulty in obtaining approval to undertake 
studies in out-of-hospital cardiac arrest victims. The inability of 
most cardiac arrest victims to provide the requisite informed consent 
has proved a significant barrier to evaluating either treatment options 
available in other countries, or new techniques devised in the United 
States (Ref. 29).
    Participants asserted that, without validation of standard 
treatment, many patients are now essentially participants in 
uncontrolled ``experiments'' when they receive emergency care. These 
``experiments,'' however, do not yield data on which progress in 
rational medical decisionmaking can be based. For example, one IRB 
would not approve a protocol for a randomized clinical trial of high 
dose versus standard dose epinephrine in cardiac arrest, even though 
some clinicians at that institution used high dose epinephrine in some 
cases and others did not. The ultimate result was that patients were 
not allocated randomly to high or standard dose (Ref. 30). The 
scientific question of which dose was better could be realistically 
addressed only in a controlled trial with subjects randomly allocated 
to each dosage level in order to assure that multiple variables caused 
by differences in physicians or other features of resuscitation 
technique did not confound the data.
    The majority of participants in the Public Forum recommended that 
NIH and FDA change their regulations so that they are clear and 
consistent and that NIH and FDA develop a new section in the 
regulations to clearly permit the waiver of informed consent for acute 
care research if certain defined conditions and safeguards are met. 
Participants recommended that a short-and long-term solution be sought 
which would permit this research to proceed. The short-term solution 
would be needed if a change in the regulations could not be 
accomplished quickly.
    Since the time of the Public Forum, the Assistant Secretary for 
Health, the NIH Director, and the Commissioner of FDA have received a 
number of letters urging NIH and FDA to clarify their regulations to 
allow for waiver of informed consent in appropriate emergency research 
circumstances. On March 31, 1995, the Coalition of Acute Resuscitation 
and Critical Care Researchers submitted a statement containing over 
1,300 signatures requesting that NIH and FDA: (1) Recognize the need 
for clinical research in emergent circumstances where informed consent 
may not be feasible; and (2) issue an interpretation of the existing 
Federal regulations to allow the performance of this research.

V. Statutory Basis for These Regulations

    Sections 505(i), 507(d), and 520(g) of the act direct the Secretary 
(and, in accordance with section 903 of the act (21 U.S.C. 394), FDA) 
to issue regulations establishing conditions under which 
investigational use of drugs and devices by qualified experts will be 
permitted. For drugs (including biological drugs and antibiotics) and 
devices, the statute specifies that the agency must include among these 
conditions that the product manufacturer or sponsor require the 

[[Page 49091]]
expert studying the product to obtain informed consent from the 
subjects or their representatives.
    The only exceptions from the informed consent requirement for drugs 
are where the investigators ``deem it not feasible or, in their 
professional judgment, contrary to the best interests'' of the subjects 
(sections 505(i) and 507(d) of the act). The language of these 
provisions makes it clear that Congress contemplated that informed 
consent could be waived in the context of placebo-controlled drug 
trials: ``[the investigators] will inform any human beings to whom such 
drugs, or any controls used in connection therewith, are being 
administered * * * and will obtain the consent of such human beings or 
their representatives, except where [not feasible or contrary to their 
best interests]'' (emphasis added). The 1962 Drug amendments, which 
included section 505(i) of the act, added the requirement that drugs be 
shown to be not only safe, but also effective through ''adequate and 
well-controlled investigations, including clinical investigations,`` by 
experts qualified to evaluate effectiveness (section 505(d) and (e)). 
Section 505(i) of the act, then, authorized FDA to establish the 
conditions for the conduct of these required studies in humans. (See 
also section 507(d) of the act.)
    The 1962 amendments were adopted following the thalidomide tragedy, 
in which women were given the drug without being informed that the drug 
was experimental, or that they were research subjects, or that the 
safety of the drug had not been established. (See generally legislative 
history discussion at 44 FR 47714-47715, August 14, 1979.) Although the 
House bill would have required informed consent in all clinical trials 
of drugs, the version reported out of Conference allowed the exceptions 
that became law (H.R. Rept. No. 2526, 87th Cong., 2d sess., October 3, 
1962, pp. 4 and 5). Professional responsibility, based on ``the 
greatest exercise of conscience,'' was accepted in permitting 
administration of investigational drugs without informed consent (108 
Congressional Record 22038, 22042-43, 87th Cong., 2d sess., October 3, 
1962).
    The only exceptions from the informed consent requirements for 
devices are where the investigator determines ``there exists a life 
threatening situation involving the human subject of such testing which 
necessitates the use of such device and it is not feasible to obtain 
informed consent from the subject and there is not sufficient time to 
obtain such consent from his representative'' (section 520(g)(3)(D) of 
the act). In addition, ``unless immediate use of the device is required 
to save the life of the human subject,'' and there is insufficient time 
to obtain the concurrence of a licensed physician not involved in the 
testing, such a physician must concur in the determination (section 
520(g)(3)(D) of the act). The exceptions to require informed consent 
are ``subject to such conditions as the Secretary may prescribe.''
    The context of this provision also is a statutory amendment 
allowing exemptions to permit investigational use to study the 
products' safety and effectiveness (section 520(g)(2)(A) of the act). 
The Medical Device Amendments of 1976, which included section 520(g), 
added a system of classifications and premarket approval for certain 
devices (section 513 of the act (21 U.S.C. 360c)). The amendments 
contemplated that, with certain exceptions, effectiveness would be 
determined based on ``well-controlled investigations, including 
clinical investigations where appropriate,'' by experts qualified to 
evaluate effectiveness (section 513(a)(3) of the act).
    Congress was explicit about the purpose of section 520(g) of the 
act: ``to encourage to the extent consistent with the protection of the 
public health and safety and with ethical standards, the discovery and 
development of useful devices intended for human use and to that end to 
maintain optimum freedom for scientific investigators in their pursuit 
of that purpose'' (section 520(g)(1)). The conditions required by 
section 520(g), then, are to be interpreted within the context of this 
stated general purpose of providing freedom to the investigators within 
ethical standards and health and safety protections.
    Both the House report on the bill containing the language that 
became law in section 520(g) of the act and the Conference report refer 
to the study by the National Commission on the Protection of Human 
Subjects concerning informed consent. (See H.R. Rept. No. 853, 94th 
Cong., 2d sess. 44 (1976); H.R. Rept. No. 1090, 94th Cong., 2d sess. 64 
(1976).) This Commission, established by the National Research Act in 
1974, was to study the basic ethical principles underlying the conduct 
of biomedical and behavioral research involving human subjects. 
Congress clearly intended HHS to act in response to the Commission's 
efforts (id.). The Commission issued numerous reports, including a 
report on Institutional Review Boards. (See generally 44 FR 47716, 
August 14, 1979 for a listing of the reports.) This IRB report stated 
that ``investigators should not have sole responsibility for 
determining whether research involving human subjects fulfills ethical 
standards. Others, who are independent of the research, must share this 
responsibility, because investigators are always in positions of 
potential conflict by virtue of their concern with the pursuit of 
knowledge as well as the welfare of human subjects of their research'' 
(43 FR 56174, November 30, 1978).
    The Commission's articulation of the basic ethical principles that 
should underlie the conduct of biomedical research involving human 
subjects is the Belmont Report, which was prepared by the National 
Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research in 1978 (44 FR 23192, April 18, 1979). In proposing 
its informed consent regulations in 1979, FDA noted the congressional 
purpose reflected in both the Drug Amendments of 1962 and the Medical 
Device Amendments of 1976, to require that biomedical research be 
conducted ``in accordance with the highest contemporary ethical 
standards'' (44 FR 47718, August 14, 1979). In interpreting sections 
505(i), 507(d), and 520(g) of the act in 1995, it remains consistent 
with congressional intent to apply the principles of the Belmont Report 
in their applications by ethicists to current research issues. As 
discussed in detail in the following section, this proposed rule to 
provide an exception from the requirement of informed consent is 
supported by contemporary application of the ethical principles of the 
Belmont Report.
    Congress did not specifically address the fact that the statutory 
language containing the informed consent exemption requirements for 
investigational devices differed from those for investigational drugs 
enacted 14 years earlier. However, as the agency discussed in proposing 
its informed consent regulations in 1979, the actual policy followed by 
FDA regarding the drug informed consent exception was very similar to 
the policy being proposed for devices (44 FR 47718). In originally 
promulgating its regulations in part 50 on the protection of human 
subjects, FDA chose to apply the same standards to drug and device 
research. In order to preclude confusion that might result from 
different systems for informed consent for drug and device research and 
to implement congressional purpose reflected in both the Drug 
Amendments of 1962 and the Medical Device Amendments of 1976 (i.e., to 
require conduct of research in accordance with contemporary ethical 

[[Page 49092]]
standards), FDA is again proposing to apply the same standards to drug 
and device research.
    Sections 505(i), 507(d), and 520(g) of the act authorize the agency 
to establish the conditions for investigational use. In the proposed 
rule, FDA would establish conditions that satisfy the statutory 
criteria for exceptions from the informed consent requirement and allow 
for safe use under ethical standards for research.
    Under sections 505(i) and 507(d) of the act, a showing that 
obtaining informed consent is not ``feasible'' is alone sufficient to 
permit an exception to the requirement. Research without informed 
consent is also authorized in drug studies based upon professional 
judgment regarding the ``best interest'' of the subjects. Under section 
520(g), informed consent is required unless there is a written 
determination that (1) ``There exists a life threatening situation 
involving the human subject of such testing which necessitates the use 
of such device,'' (2) ``it is not feasible to obtain informed consent 
from the subject,'' and (3) ``there is not sufficient time to obtain 
such consent from his representative.'' In addition, a licensed 
physician who is not involved in the testing must agree with this 
three-part determination unless there is not sufficient time to obtain 
such concurrence. Consequently, circumstances that satisfy the 
statutory informed consent exception criteria for investigational 
devices will also satisfy the criteria for investigational drugs.
    The exception from the informed consent requirement permitted by 
the proposed rule would be conditioned upon various findings by an IRB. 
First, the subjects must be in a situation that is: (1) Life-
threatening, (2) where available treatments are unproven or 
unsatisfactory, and (3) the collection of valid scientific evidence is 
necessary to determine the most beneficial intervention 
(Sec. 50.24(a)(1)). In addition, the opportunity to be in the study 
must be in the interest of the subject because the life-threatening 
situation necessitates intervention and the risk of the study is 
reasonable in light of the medical condition and what is known about 
the risks and benefits of current therapy and of the investigational 
intervention (Sec. 50.24(a)(3)). With regard to the study itself, it 
must be research that could not practicably be carried out without the 
informed consent waiver (Sec. 50.24(a)(4)).
    These conditions satisfy the criterion included in sections 505(i) 
and 507(d) of the act regarding the best interest of the subject. They 
also satisfy the criteria in section 520(g) of the act that the subject 
be in a ``life threatening situation'' which ``necessitates the use of 
such device.'' The proposed rule would limit the exception to the 
narrow circumstance in which both (1) intervention is needed because of 
the subject's medical condition, and (2) the collection of valid data 
is needed because of the absence of proven satisfactory available 
treatment for the condition. The proposed rule thus gives double weight 
to the statutory ``necessitates'' criterion.
    The agency's proposed implementation of the ``necessitates'' 
criterion also would permit administration of either the test product 
or a control product, in keeping with the legislative intent to permit 
scientific investigation to demonstrate safety and effectiveness. 
Randomized placebo-controlled or active-controlled studies may be 
needed to demonstrate the effectiveness of products for life-
threatening, as well as nonlife-threatening, conditions. As discussed 
in more detail below, this interpretation is also consistent with the 
ethical principles in the Belmont Report. For example, the principle of 
beneficence supports research that ultimately ``makes it possible to 
avoid the harm that may result from the application of previously 
accepted routine practices that on closer investigation turn out to be 
dangerous'' (Belmont Report, 44 FR 23192 at 23194, April 18, 1979).
    In issuing current Sec. 50.23(a), permitting exceptions from 
obtaining informed consent, the agency included an additional criterion 
not required by section 520(g)(3)(D) of the act (44 FR 47720, August 
14, 1979). This provision of the regulation, codified at 
Sec. 50.23(a)(4), was added ``to prevent routine reliance on the 
exception'' (44 FR 47720, August 14, 1979). In final form, this 
subsection required that ``[t]here 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.'' The proposed 
new Sec. 50.24(a) would permit use of the test product when there is an 
alternative unproven or unsatisfactory therapy in general use that may 
be equally likely to save the subject's life. Section 50.24(a)(3) would 
allow for ``reasonable'' risk, given what is known about the risks and 
benefits of the test product, the alternative therapy, and the medical 
condition. The narrowly circumscribed situation described in 
Sec. 50.24, as well as additional safeguards, such as public disclosure 
prior to beginning the study, protects against ``routine reliance'' on 
this exception to conduct research without informed consent.
    Section 50.24 also would require, in accordance with the criterion 
in sections 505(i), 507(d), and 520(g) of the act, that obtaining 
informed consent not be ``feasible.'' This regulation would restrict 
determinations of infeasibility to those situations in which: (1) The 
subjects are unable to give consent because of their medical condition, 
(2) the product must be administered before it is feasible to obtain 
consent from legally authorized representatives, and (3) individuals 
likely to be eligible cannot reasonably be identified prospectively 
(Sec. 50.24(a)(2)). Thus, section 50.24(a)(2) also incorporates the 
required criterion of section 520(g) that there be insufficient time to 
obtain consent from a representative.
    Section 50.24 would require approval of the protocol by an IRB, 
which is also required to have at least one member who is a licensed 
physician not otherwise involved in the research protocol (or such a 
consultant) who concurs with the protocol. That physician's concurrence 
is in keeping with the provision of 520(g)(3)(D) for concurrence by 
such an individual that the criteria for testing without informed 
consent have been satisfied. In most, if not all, instances under 
Sec. 50.24 there will be a need for ``immediate use'' to save the 
subject's life and not sufficient time following the onset of the life-
threatening condition to obtain the concurrence by an independent 
physician and, therefore, there will be no statutory requirement for 
such concurrence. Nevertheless, the agency believes that concurrence 
with the protocol by an independent physician associated with the IRB 
is another valuable protection for the subject and additional assurance 
that the statutory intent of independent physician concurrence will be 
satisfied.
    For the reasons discussed above, the provisions of Sec. 50.24 
satisfy all of the statutory criteria of sections 505(i), 507(d), and 
520(g) of the act for permitting exceptions to the informed consent 
requirements for investigational drug and device uses.
    Section 50.24 also contains additional protections for the health 
and safety of the research subjects (e.g., establishment of an 
independent data and safety monitoring board), as authorized by, and in 
keeping with the purposes of sections 505(i), 507(d), and 520(g) of the 
act. This proposed regulation is also authorized by section 701(a) of 
the act, which provides general authority to issue regulations for the 
efficient enforcement of the act.

[[Page 49093]]

    The conforming amendments to regulations governing drug and device 
investigations and marketing are authorized by sections 502, 503, 505, 
506, 510, 513, 514, 515, 516, 518, 519, 520, 701, and 801 of the act 
and section 351 of the Public Health Service Act (21 U.S.C. 352, 353, 
355, 356, 360, 360c, 360d, 360e, 360f, 360h, 360i, 360j, 371, and 381, 
and 42 U.S.C. 262)

VI. Ethical Basis for These Regulations

    In developing this proposed regulation, FDA has carefully 
considered the basic ethical principles that underlie research to 
ensure that it is consistent with those principles. The agency is 
convinced that the research described in this section is ethically 
permissible.
    The current FDA and HHS IRB and informed consent regulations are 
based, in large part, on the ethical principles discussed in the 
Belmont Report. As discussed in that report, the three basic ethical 
principles that are relevant to research involving human subjects are 
the principles of respect for persons, beneficence, and justice.
    The principle of respect for persons incorporates two general rules 
of ethical behavior: (1) Competent individuals must be treated as 
autonomous agents, that is to say, persons who are legally and morally 
competent to understand the risks and benefits of a proposed research 
activity must provide prior, uncoerced informed consent before they may 
be enrolled as research subjects; and (2) persons whose autonomy is 
absent or diminished may participate in research only if additional 
protections are provided for them. The proposed rule recognizes that 
subjects who are candidates for emergency research will not meet the 
condition of being fully competent. In many cases, they will be totally 
incompetent. Such potential subjects, if they are to be enrolled in 
research, must be provided with special additional protections. The 
special protections proposed in this rule for subjects of emergency 
research include prior FDA and community consultation on the research, 
public disclosure, and careful mandatory oversight of the welfare of 
subjects by a data and safety monitoring board. These special 
protections are described below.
    The principle of beneficence requires that the risks associated 
with a research activity are reasonable in the light of expected 
benefits and it also requires that the chance for benefits from 
participation be maximized, and the risk of possible harms be 
minimized, consistent with sound research design.
    The principle of justice requires that the burdens and benefits of 
participation in research be equitably distributed across the entire 
population in the place or region where the research is conducted. That 
means, in general, that racial, ethnic, gender, and economic status 
should not be used as exclusion criteria for participation in research. 
It further means that persons who are eligible for participation in the 
research because of their disease or condition, should be provided 
reasonable opportunity to participate in research until the research 
cohort is fully recruited. Experience has repeatedly shown that 
requiring surrogate consent from legally authorized representatives 
tends to inhibit equitable inclusion in the study because surrogate 
consent is more easily obtained from family members of Caucasians than 
from family members of minorities, and it is more easily obtained from 
family members of middle and upper income persons than from persons of 
lower income (Ref. 31). Waiving the requirement for informed consent 
from potential subjects and their surrogates helps to provide for an 
equitable distribution of both burdens and benefits of emergency 
research in a manner that meets the requirements of justice.
    The Belmont Report notes that ``[t]hese principles cannot always be 
applied so as to resolve beyond dispute particular ethical problems. 
The objective is to provide an analytical framework that will guide the 
resolution of ethical problems arising from research involving human 
subjects.'' (44 FR 23193, April 18, 1979.) The Belmont Report did not, 
therefore, address resolution of conflicts among these ethical 
principles that might be occasioned by a particular research protocol, 
but it did provide a framework within which conflicts among the 
principles could be resolved.
    The National Commission did not explicitly address the issue of 
research involving the comatose patient. However, in March 1983, the 
President's Commission for the Study of Ethical Problems in Medicine 
and Biomedical and Behavioral Research issued its ``Second Biennial 
Report on the Adequacy and Uniformity of Federal Rules and Policies, 
and of their Implementation, for the Protection of Human Subject.'' In 
its report, the President's Commission identified research on the 
comatose as an issue worthy of further consideration. In its 
discussion, it noted that
    It is settled law that physicians and hospitals may assume that 
an emergency patient would consent to life-saving treatment; such 
treatment may therefore be initiated without express consent. The 
legal principle is based, however, on the provision of standard 
care. It is not so clear, however, whether one should assume that an 
emergency patient would consent to participation in research on new 
or experimental treatment.
(Ref. 32)
    The agency has considered the ethical principles set forth in the 
Belmont Report in the formulation of this rule. It has also engaged in 
extended public dialogue to resolve the difficulty noted by the 
President's Commission. The exception from informed consent for 
investigations involving life-threatening conditions would apply only 
to subjects not in a position to exercise autonomy. These subjects will 
be in a life-threatening situation which necessitates emergency 
intervention. Thus, in accord with the principle of respect for 
persons, persons in these situations are entitled to special 
protection.
    In emergent situations, protection is provided and the principle of 
respect for persons is satisfied if, in circumstances of clinical 
equipoise, either the test therapy or its historic alternative is 
provided, even without specific consent. When 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, according to testimony 
presented at the January 1995 FDA/NIH Public Forum on Informed Consent 
in Clinical Research Conducted in Emergency Circumstances, whenever at 
least a reasonable minority of medical professionals believe the 
experimental treatment would be as good as, or better than, the 
standard treatment (Ref. 23).
    This proposed rule is also consistent with the principle of 
beneficence. The principle of beneficence maximizes possible benefits 
and minimizes possible harms. In order to avoid harm, one must know 
what is harmful. In emergency medicine, the standard of care may not 
have been validated--it may be beneficial or it may be harmful. The 
principle of beneficence dictates that knowledge be gathered when there 
is clinical equipoise between established and proposed interventions, 
through the conduct of research. Beneficence can be assured by the 
collection of valid scientific evidence, including evidence derived 
from randomized controlled clinical trials, in order to determine 
whether the particular intervention is beneficial. Harms are minimized, 
in part, by careful monitoring of the study by an independent data and 
safety monitoring board that regularly compares study 

[[Page 49094]]
data with preestablished ``stopping rules'' designed to terminate the 
study before any serious harm occurs.
    The principle of justice is also pertinent to this proposed rule. 
Systematically excluding persons who are unable to give informed 
consent and who have no surrogate to consent for them from research may 
be discriminatory, as noted above. An inability to consent, or lack of 
an authorized representative, should not in itself be a reason for 
excluding persons from participating in potentially beneficial and 
scientifically well-designed, controlled, studies (Refs. 33 and 34).

VII. Description of the Proposed Rule

A. Introduction

    Section 50.24 will be applicable only to that limited subset of 
research activities that involve individuals who are in a life-
threatening situation and for whom available treatments are unproven or 
unsatisfactory (e.g., have poor clinical outcome or leave individuals 
with substantial mortality or major morbidity). FDA believes that 
evidence submitted at the Public Forum on the chilling effect of 
current regulations on the care and medical management of such persons 
in life-threatening situations, including impairing their access to 
potentially life-saving therapy, justifies the prompt issuance of 
regulations governing research on such subjects. Thus, FDA intends to 
issue a final rule, responding to comments received on this proposed 
rule, promptly following the 45-day comment period.

B. Scope

    Section 50.24(d) will require that all protocols that involve a 
product regulated by FDA and that involve the possibility of invoking 
an exception under this section are to be performed under a separate 
IND or a separate Investigational Device Exemption (IDE).
    For medical devices, this means that a sponsor may not submit the 
investigation to an IRB as a nonsignificant risk device (21 CFR 
812.2(b)). All device investigations are to be submitted to the agency 
as separate IDE's, prominently identified as IDE's that propose to 
invoke the exception in this rule. If the sponsor has already submitted 
an IDE to the agency for the medical device, the sponsor may cross-
reference information in that IDE. The purpose of proposing to require 
a separate IDE is to ensure that there are 30 days before commencement 
of the trial in order to permit agency review of the protocol and 
supporting information.
    For drugs, this means that the exemptions from the requirement to 
submit an IND, contained in 21 CFR 312.2(b), may not be invoked for 
investigations of a drug product that is lawfully marketed in the 
United States if the investigation involves potential invoking of 
Sec. 50.24. The agency believes that investigations that propose to 
involve individuals who are unable to give informed consent do not meet 
the requirements of Sec. 312.2(b)(iii), i.e., the use in this subject 
population would increase the risks or decrease the acceptability of 
the risks associated with the use of the drug product and, therefore, 
agency review of the IND is appropriate. All drug investigations will 
be submitted to the agency as separate IND's, prominently identified as 
IND's that propose to invoke the exception in this rule. If the sponsor 
has already submitted an IND to the agency for the drug product, the 
sponsor may cross-reference information in that IND. The purpose of 
proposing to require a separate IND is to ensure that there are 30 days 
before commencement of the trial in order to permit the agency to 
review the protocol and supporting information.

C. IRB Responsibilities

    Section 50.24(a) gives the IRB the primary responsibility for 
determining that the research meets the requirements of this proposed 
rule. In the Coalition's consensus statement, the Coalition recommended 
that the interests, rights, and welfare of subjects in emergency 
research trials be protected by special safeguards applied by IRB's. It 
recommended further that because IRB's have good insight into local 
practice, subject populations, and the capabilities of researchers, 
institutions and resources, that IRB's should be the primary unit 
responsible for maintaining oversight of these clinical trials. The 
majority of participants at FDA/NIH Public Forum also expressed support 
for this responsibility being placed on IRB's.
    At the congressional hearing and at the Public Forum, some 
individuals expressed concern about placing this responsibility with 
IRB's that charge for their services and that are not physically 
located where the research is to be conducted, so called, ``independent 
IRB's.'' The agency has considered these concerns, but believes that 
duly constituted IRB's that fulfill the requirements of part 56 (21 CFR 
part 56) and Sec. 50.24, including paragraph (a)(5) which will require 
consultation with the communities from which the subjects will be drawn 
and public disclosure, will ensure that the rights and welfare of 
research subjects are protected. The agency has permitted independent 
IRB's to review research since 1981. The agency has acknowledged that 
independent IRB's that lack members from the area of the research site 
may have difficulty acquiring knowledge of community attitudes, 
information on conditions surrounding the conduct of the research, and 
the continuing status of the research. FDA has advised these IRB's, at 
conferences and in written educational materials, to be particularly 
sensitive to meeting all requirements of the regulations.
    This regulation would permit the IRB to approve research without 
requiring that informed consent be obtained if the IRB determines and 
documents that it is approving such research for the reasons given in 
Sec. 50.24(a).

D. IRB Documentation

    This regulation will require the IRB to document that it considered 
each element in Sec. 50.24(a) and found that each element was met by 
the proposed research. The agency believes that this documentation is 
necessary to ensure that the IRB is adequately protecting the rights 
and welfare of human subjects.
    Under Sec. 50.24(e), an IRB would be required to document its 
findings when it cannot approve the research either because the 
research does not meet the criteria in Sec. 50.24 or because of other 
relevant ethical concerns. The IRB is to provide this information in 
writing to the research sponsor. The sponsor of the research must share 
this information with FDA, and investigators, and other IRB's that are 
asked to review this or a substantially equivalent trial. FDA believes 
that sharing IRB information with these entities concerned with the 
study will enhance the protection provided to research subjects by 
establishing communication among IRB's on this important issue. IRB 
concerns about the approvability of studies may identify to the sponsor 
and FDA issues that need to be addressed in the research such as the 
need to alter the study design to better protect the rights and welfare 
of research subjects. The sponsor's sharing of these concerns with 
other investigators and IRB's that are asked to review this or 
substantially equivalent research, assures that all relevant IRB's and 
investigators will be aware of concerns noted by other IRB's and will 
have the opportunity to assess those concerns in their review of the 
research activity.
    Because IRB's that review FDA-regulated research may be 
institutionally-based, independent of an 

[[Page 49095]]
institution, commercial, established by the sponsor of the research, or 
established by a group of investigators, it is possible for an 
investigator to seek approval of an investigation from more than one 
IRB. Thus, if the study is disapproved by one IRB, it is possible for 
the investigator to seek approval from another. The agency believes 
that the provision requiring the sharing of information will enable any 
IRB that is asked to review the study to take into account relevant 
ethical concerns raised by another IRB.
    This requirement would not add an additional documentary burden to 
IRB's because under Sec. 56.115(a)(2), the IRB is required to document 
the basis for disapproving any proposed research and to prepare a 
written summary of the discussion of controverted issues and their 
resolution. The proposed requirement in Sec. 50.24(c), for IRB 
retention of records and for their availability during an inspection, 
is identical to that required for records maintained pursuant to part 
56.

E. Criteria for IRB Approval

    Section 50.24(a)(1) would require that the IRB determine that:
    * * * 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 trials, is necessary 
to determine what particular intervention is most beneficial.
    The agency believes that an IRB can determine that the subjects are 
in a life-threatening situation if it determines that the medical 
condition being treated by the proposed intervention poses an imminent 
risk of loss of life. FDA considers treatments to be unproven when, for 
example, their safety and effectiveness have not been established in 
adequate and well-controlled clinical trials. FDA believes that 
unsatisfactory treatments include those treatments which fail to 
prevent a significant proportion of deaths or permanent disabilities in 
the population of interest. As discussed earlier, in order to learn 
what is harmful or beneficial, the intervention or activity must be 
subjected to adequate and well-controlled trials, including, where 
appropriate, trials involving a placebo. Determining the risks and 
benefits of intervention for potentially life-saving therapies will 
enable physicians to better evaluate the appropriate treatment for 
individual patients.
    As the Coalition noted in its consensus statement:
    Patients deserve and expect modern, safe, and effective medical 
care when they are acutely ill or injured. We believe the public 
desires advances in acute emergency and critical care and 
understands that research is required to improve medical care. The 
benefits of emergency research include potential improvement in 
survival and the quality of life following many life threatening 
conditions that otherwise would have dismal outcomes. The risk of 
not doing emergency research is denying promising new treatments to 
individual patients with conditions that currently have no effective 
therapy, or to future patients with the same devastating condition.
(Ref. 22.)
    Section 50.24(a)(2) defines when obtaining informed consent is not 
feasible. The agency believes that the first criterion 
(Sec. 50.24(a)(2)(i)) generally will be met if, once the medical 
condition develops, the potential subjects would not be able to give 
informed consent as a result of the medical condition. Examples of 
situations in which obtaining informed consent from the subject may not 
be feasible include individuals who have suffered a cardiac arrest, 
severe head injury, or other catastrophic medical or traumatic event.
    Section 50.24(a)(2)(ii) would require the IRB to determine that it 
is necessary to administer the intervention before it is feasible to 
obtain informed consent from a legally authorized representative. It 
would require the IRB to consider the consequences of waiting to 
administer the intervention until a legally authorized representative 
can consent on behalf of the subject. This criterion recognizes the 
Coalition's concern that ``the test therapy for these catastrophic 
conditions must be given immediately after the acute injury or illness 
to have any possibility of benefit.'' If the window of time is narrow, 
it will be difficult or impossible to identify a legally authorized 
representative especially for patients whose identities are unknown at 
the time of presentation.
    Section 50.24(a)(2)(iii) would require the IRB to determine that 
there is no reasonable way to identify prospectively the individuals 
likely to become eligible for the research because the emergence of the 
condition to be studied cannot be predicted reliably in particular 
individuals. The agency believes that when there is a reasonable way to 
prospectively identify such individuals, that efforts should be made to 
obtain prospective consent for the particular protocol from those 
subjects.
    Section 50.24(a)(3) describes why the research intervention is in 
the best interests of subjects. As discussed earlier, the agency 
expects clinical equipoise to exist in protocols that would be approved 
under this section. Clinical equipoise exists when the relative 
benefits and risks of the proposed intervention are unknown, or thought 
to be equivalent or better than standard therapy. Clinical equipoise 
has been described as existing when at least a reasonable minority of 
medical professionals believe the test article is as good as or better 
than the standard treatment or that the standard treatment to be tested 
is no better than placebo. The agency expects that evidence from animal 
studies, previous use in humans (for other indications), similarity to 
other products used in humans, and other evidence, could be used to 
document clinical equipoise.
    Section 50.24(a)(4) would require the IRB to determine that the 
study could not practicably be conducted without the waiver. This 
regulation will not permit waiver of informed consent in instances in 
which an individual may be unconscious or otherwise incompetent to give 
informed consent, but immediate intervention is not needed in order to 
prevent death because there is sufficient time to locate, and obtain 
consent from, a legally authorized representative. In those instances, 
it may be possible to delay treatment until a court appointed patient-
advocate is arranged, the consent of a family member can be obtained, 
or some other procedure for a surrogate can be followed. There are also 
medical conditions that predictably occur in given identifiable subject 
populations. In those cases, it is possible to obtain advance consent 
before the intervention is required. In other cases, such as events 
that occur regularly in already hospitalized, acutely ill patients, the 
majority of subjects will have a family member or a legally authorized 
representative readily available to provide consent. In these 
instances, the research may, in accord with the provisions of the law 
of the jurisdiction, proceed without invoking a waiver of informed 
consent. In cases such as these, it will be inappropriate to invoke 
this exception.
    The agency recognizes that there may be situations where research 
studies that would be conducted under Sec. 50.24(a) may include a 
limited number of subjects for whom a representative is able to provide 
surrogate consent for the subject, and the treatment window may be such 
to permit such consent to be obtained. In anticipation of this 
possibility, the IRB will be required to have reviewed and approved an 
informed consent document in accord with Sec. 56.109(b), so that 
surrogate consent can be obtained for those subjects.
    Section 50.24(a)(5) describes four ``additional protections'' that 
would have to be provided for each protocol: 

[[Page 49096]]
consultation with representatives of the communities from which the 
subjects will be drawn; public disclosure prior to the commencement of 
the study sufficient to describe the study and its risks and benefits; 
public disclosure of sufficient information following completion of the 
study to apprise the community and researchers of the study and its 
results; and the establishment of an independent data and safety 
monitoring board. In addition to these protections, the IRB should 
consider whether there are other appropriate additional protections 
that should be included to protect the rights and welfare of these 
subjects.
    In order to provide for consultation with representatives of the 
communities from which the subjects will be drawn, and to supplement 
the information available for review by the IRB, all IRB's should 
consider, for example, having the clinical investigator or sponsor 
convene a public meeting in the community on 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 additional members who are not affiliated with the 
institution and are representative of the community; or developing some 
other mechanism to ensure community involvement and input into the 
IRB's decisionmaking process.
    In order to provide for public disclosure, the IRB should consider 
how best to publicly disclose, prior to the commencement of the study, 
sufficient information to describe the study's risks and benefits, 
e.g., relevant information from the investigator's brochure or study 
protocol. Public disclosure following IRB review should be sufficient 
to disclose information concerning the IRB's resolution of issues and 
final decisions; this disclosure should provide community confidence in 
the role of the IRB and in its decisionmaking capability. Disclosure 
following completion of the study should provide sufficient information 
to the community about its results and sufficient information to 
researchers, which would include the underlying data, to be able to 
assess the results of the study.
    The agency recognizes that the level of disclosure to 
representatives of the community and to researchers that would be 
required by Sec. 50.24(a)(5) would require sponsors to disclose 
information about an investigation which they might not otherwise 
publicly disclose. FDA would require sponsors to provide copies to FDA 
of the publicly disclosed information for any investigation which 
proposes an exemption from the informed consent requirement. The agency 
believes that by disclosing the information described in this 
paragraph, the community will better understand the nature of the 
research and the rights and welfare of subjects will be better 
protected. By 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 to obtain the same level of 
scientific knowledge and to advance emergency medicine.
    Requiring an independent data and safety monitoring board would 
help ensure that if it becomes clear that risks are greater than 
anticipated, or that the benefits do not justify the risks of the 
research, the IRB is informed and can act on the information. For 
multi-center studies, the agency generally would expect the sponsor of 
the research, rather than the IRB, to establish the independent data 
and safety monitoring board. By ``independent,'' the agency intends 
that the board be composed solely of individuals who have no financial 
interest in the outcome of the study, and who have not been involved in 
the design or conduct of the study. Section 56.111(a)(6) currently 
requires the IRB to determine that, where appropriate, the research 
plan makes adequate provision for monitoring the data collected to 
ensure the safety of subjects. As discussed in the preamble to the 
January 27, 1981, regulations, in response to comments questioning the 
meaning of Sec. 56.111(a)(6) and requesting guidelines for determining 
at what point in each experiment one treatment is shown to be safer and 
more effective than alternative treatments or no treatments, FDA 
responded:
    This [data monitoring] procedure might be an appropriate 
requirement in large scale clinical trials or in studies with a high 
degree of risk. The IRB may require the use of data safety 
monitoring boards in order to meet the requirements of this 
provision. Thus, if it becomes clear that risks are greater than 
anticipated, or that the benefits do not justify the risks of the 
research, the IRB is informed and can act on the information. This 
provision matches the HHS requirement * * *. IRB's generally will 
not have the scientific competence to make such a judgement [at what 
point in each experiment one treatment is shown to be safer and more 
effective than alternate treatments or no treatment]. The 
determination whether and at what point in an investigation a test 
article has been shown to be safe and effective in accordance with 
the requirements of the act is a determination that must be made by 
the investigator, the sponsor, and, ultimately, FDA.
(46 FR 2869, January 27, 1981)
    Section 50.24(b) describes a hierarchy of persons who should be 
informed of the subject's inclusion in the study, about the details of 
the study, and that the subject can discontinue participation at any 
time without penalty or loss of benefits to which the subject is 
otherwise entitled. The hierarchy is, first, the subject; if the 
subject remains incapacitated, then a legally authorized representative 
of the subject; if the representative is not available, a member of the 
subject's family is to be informed. The agency has included the phrase 
``without penalty or loss of benefits to which the subject is otherwise 
entitled'' to ensure, in part, that a subject who is withdrawn from a 
study is provided with appropriate alternative medical care consistent 
with that person's medical condition.
    The definition of ``family members'' in Sec. 50.3(n) was taken from 
the Federal Government's Office of Personnel Management's final rule 
which relates, in part, to the use of sick leave to care for family 
members. That rule implements the Federal Employees Friendly Family 
Leave Act (Pub. L. 103-388), and was published in the Federal Register 
of December 2, 1994 (59 FR 62266). The definition has been modified by 
the phrase ``legally competent'' to acknowledge that family members 
must be not only of legal age, but also possess appropriate mental 
capacity, to have this information meaningfully conveyed to them.

F. Preemptive Effect

    In developing these proposed 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 believes that it is important 
that informed consent requirements governing this type of research be 
nationally uniform, particularly in light of the current confusion 
created in the research community by differing Federal regulations. FDA 
recognizes, however, 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 which may otherwise be applicable and which provide 
additional protections for human subjects. Accordingly, FDA 
specifically invites 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 

[[Page 49097]]
authorized by IRB's acting in accord with these proposed rules and 
whether any such requirements should be preempted by Federal 
requirements.

VIII. Effective Date

    FDA is proposing to make these regulations effective on the date of 
publication of the final rule in the Federal Register because of the 
urgent need to permit emergency research to proceed. The agency 
believes that it is in the public interest to have a final rule in 
place as quickly as possible. By permitting certain controlled clinical 
trials to be conducted with the involvement of human subjects who are 
confronted by a life-threatening condition and who are also unable to 
give informed consent because of that condition, the agency expects to 
provide individual access to potentially beneficial treatment. The 
agency also expects that research to result in advancement and 
improvement of therapies used in emergency medicine situations that 
currently have poor clinical outcome. As a result of this rule, many 
individuals confronted by life-threatening situations will benefit 
immediately. Survival of these individuals may be enhanced by their 
participation in controlled trials. Therefore, FDA tentatively 
concludes that there is good cause to dispense with the normal 30-day 
period between publication of a final rule and its effective date.

IX. Request for Comments

    Interested persons may, on or before November 6, 1995 submit to the 
Dockets Management Branch (address above) written comments regarding 
this proposal. Comments are also solicited regarding the need for 
Federal preemption (see sections VII.F. and XI.B. of this document) and 
information collection requirements subject to Office of Management and 
Budget (OMB) approval under the Paperwork Reduction Act of 1995 (see 
section XIII. of this document). Two copies of any comments are to be 
submitted, except that individuals may submit one copy. Comments are to 
be identified with the docket number found in brackets in the heading 
of this document. Received comments may be seen in the office above 
between 9 a.m. and 4 p.m., Monday through Friday. Comments on 
information collection requirements should be directed to FDA's Dockets 
Management Branch (address above) and to OMB's Office of Information 
and Regulatory Affairs (addressed below in section XIII. of this 
document).
    FDA believes that a comment period greater than 45 days would be 
contrary to the public interest for the reasons given above. In 
addition, FDA is taking this action in response to the congressional 
hearing, the Consensus Conference, FDA/NIH Public Forum, and to public 
and professional concerns that not all of what has become standard and 
accepted medical therapy for use in acute or resuscitation care has 
been subjected to controlled clinical trials to establish its safety or 
effectiveness.
    Currently, there are some investigations ongoing involving life-
threatening conditions which enroll only subjects able to consent; 
other investigations are on hold pending issuance of this regulation. 
In those trials that are ongoing, accrual of subjects is exceedingly 
slow. Further delay could cause sponsors and funding institutions to 
cease support of such research, resulting in the research being stopped 
before sufficient data is gathered to demonstrate efficacy. FDA 
believes that extending the comment period would delay implementation 
of this rule and would result in the cessation of some of these studies 
or in the diversion of emergency research resources to other 
activities. As a result, potential subjects would be deprived of the 
opportunity to obtain potentially life-saving treatment. In addition, 
society would suffer as a result of this discontinuity in research by 
not being able to determine the effectiveness of potentially life-
saving therapies.
    Because of these public health concerns, FDA does not intend to 
extend the comment period beyond that date. Also, the agency is 
advising that it may not be able to consider any comments received at 
the Dockets Management Branch after the close of business on November 
6, 1995. Although FDA is providing 45 days, rather than 90 days, for 
comments on this subject through the routine notice and comment 
procedures, it has received much input through the various conferences 
and congressional hearings discussed above and in correspondence. This 
input has come from IRB's, sponsors, investigators, ethicists, patient 
groups, etc.
    The agency considered whether a reinterpretation of its existing 
regulations would meet the needs of persons in life-threatening 
situations and the research community. It concluded against such a 
reinterpretation for a number of reasons, including: it would not make 
the FDA regulations and the HHS regulations congruent; it would not 
provide prospective protections to subjects participating in such 
research; it would be difficult if not impossible to enforce additional 
safeguards that the agency believes are essential to protect subjects 
involved in such research activities; and it would not adequately 
eliminate the confusion that currently exists within the research 
community as to the standards that must be applied to this research. 
The sole benefit of a reinterpretation of existing regulations would be 
to permit this limited class of research to move forward quickly, 
rather than delaying until a new regulation could be written. The 
agency has, thus, placed priority on developing this proposed 
regulation in order to permit the ethical conduct of a limited class of 
emergency research.

X. 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.

XI. 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 
proposed 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 proposed 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 proposed 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 proposal is consistent with the 
principles set forth in Executive Order 12612.
    Executive Order 12612 states that agencies formulating and 
implementing 

[[Page 49098]]
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 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, through this 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 requests information and comments from interested parties, 
including but not limited to State and local authorities, on these 
issues of federalism.

XII. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-395). 
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 proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because this rule is a deregulatory action insofar 
as it will permit research to proceed which could not proceed under 
existing regulations, and because relatively few research projects will 
need to meet the requirements of this rule, the agency certifies that 
the proposed 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.

XIII. Paperwork Reduction Act of 1995

    This proposed rule contains only information collection 
requirements which are subject to review by the OMB under the Paperwork 
Reduction Act of 1995 (Pub. L. 104-13), and which are already approved 
under Protection of Human Subjects--Recordkeeping Requirements for 
Institutional Review Boards, 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 
under OMB Control No. 0910-0078. Modifications to these approved 
information collection requirements are underway.
    For Protection of Human Subjects--Recordkeeping Requirements for 
Institutional Review Boards (IRB) under OMB Control No. 0910-0130, FDA 
has calculated the existing recordkeeping burden on IRB's 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 which 
propose to invoke this exception from informed consent will increase 
for an estimated 200 IRB's by 5 annual hours per record-keeper. This 
will change the estimated recordkeeper burden from 65 to 70 hours 
annually.
    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, this proposal discloses the 
agency's intent to require 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. Currently, 
the agency estimates the reporting requirements contained in part 312 
to average 123.34 hours per respondent annually. FDA estimates that 
respondents will increase by 400 annually, resulting in an increase of 
49,336 hours over that currently estimated. The reporting burden for 
respondents will, as a result, increase from an estimated 3,926,308 
hours annually to 3,975,644 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) 
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 trial or a substantially equivalent 
trial, and other IRB's that are asked to review the trial or a 
substantially equivalent trial. In accord with the Paperwork Reduction 
Act of 1995, this proposal discloses the agency's intent to require 
this third party notification.
    For recordkeeping, the agency estimated that an average of 165.13 
hours were spent per respondent. For the estimated additional 400 
recordkeeping respondents invoking this rule, this would result in 
approximately 66,072 hours annually. The recordkeeping burden for 
respondents will, as a result, increase from an estimated 2,244,090 
hours annually to 2,310,162 hours annually.
    For Investigational Devices Exemption Reports and Records under OMB 
Control No. 0910-0078, the agency estimates that 10 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 may, therefore, increase from 244 original submissions to 254 
original submissions, increasing the number of hours by 800 for 
respondents (estimated at 80 hours per submission), from a total of 
19,520 to 20,320 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 trial or a substantially equivalent 
trial, and other IRB's that are asked to review the trial or a 
substantially equivalent trial. In accord with the Paperwork Reduction 
Act of 1995, this proposal discloses the agency's intent to require 
this third party notification.
    The number of recordkeepers 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 100 hours. 
The agency had estimated that original submissions 

[[Page 49099]]
require 10 hours annually of recordkeeping per submission; 
recordkeeping related to protocols invoking this rule are expected to 
increase the submissions from 244 to a total of 254.
    As required by section 3507(d) of the Paperwork Reduction Act of 
1995, FDA has submitted a copy of this proposed rule to OMB for its 
review of these previously approved information collection 
requirements. The agency solicits comments on the information 
collection requirements in order to: (1) Evaluate whether the proposed 
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 proposed 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. Organizations and individuals 
desiring to submit comments on the information collection requirements 
should direct them to FDA's Dockets Management Branch (address above) 
and to the Office of Information and Regulatory Affairs, OMB, rm. 
10235, New Executive Office Bldg., 725 17th Street, N.W., Washington, 
DC 20503, Attention: Desk Officer for FDA.

XIV. Conforming Amendments

    This proposed rule would necessitate a number of changes to the 
regulations for human drugs, biologics, devices, and institutional 
review boards so that those regulations are consistent with this rule.

A. Amendments to Regulations for IRB's

    FDA is proposing to amend Sec. 56.109(c) to expressly recognize 
that IRB's may approve studies for which informed consent is not 
obtained when the requirements in Sec. 50.24 are met. FDA is also 
proposing to amend Sec. 56.109 to specify in the IRB regulations the 
requirement to notify sponsors when an IRB determines it cannot approve 
such studies and to notify sponsors when public disclosure of these 
studies has occurred. In addition, FDA is proposing to revise 
Sec. 56.111 to reference the IRB's need to find that the criteria set 
forth in Sec. 50.24 are met before approving investigations involving 
an exception from informed consent under Sec. 50.24.

B. Amendments to Regulations for Human Drug Products

    The proposed amendment to Sec. 312.2(b) (21 CFR 312.2(b)) makes 
clear that these studies are not exempt from the requirements of part 
312 (21 CFR part 312). Proposed Sec. 312.20(a) and the amendments to 
Sec. 312.30 would codify in the IND regulations the requirement for a 
separate IND for studies under Sec. 50.24. Proposed new Sec. 312.23(f) 
contains the requirement referenced in Sec. 50.24(d) that sponsors 
prominently identify these studies in separate IND's. FDA is proposing 
to add new Sec. 312.54 to specify the need for sponsors to actively 
monitor the progress of proposed investigations so that appropriate 
public disclosure can occur and so that other IRB's, investigators, and 
FDA are notified of an IRB determination that it cannot approve the 
investigation. Section 312.60 would be amended to reference the 
exception from informed consent in Sec. 50.24. The amendment to 
Sec. 314.430(d) (21 CFR 314.430(d)) would acknowledge that studies 
involving Sec. 50.24 will not proceed without public discussion. 
Section 314.430(d) would be amended to codify that sponsors identify 
the information publicly disclosed.

C. Amendment to Biologics Regulations

    FDA is proposing to amend 21 CFR 601.51(d) for the reasons set 
forth above for Sec. 314.430(d).

D. Amendment to Device Regulations

    FDA is proposing to amend Secs. 812.20 and 812.35(a) (21 CFR 812.20 
and 812.35(a) to codify in the IDE regulations the requirement for 
filing a separate IDE for studies under Sec. 50.24. Section 
812.20(b)(13) would be amended to codify the need to clearly identify 
in the IDE submission that the study involves an exception from 
informed consent under Sec. 50.24. The amendment to Sec. 812.38(b)(2) 
would acknowledge that studies involving Sec. 50.24 will not proceed 
without public discussion. Section 812.38(b) would be amended to codify 
that sponsors identify the information publicly disclosed.
    New Sec. 812.47 would specify the need for the sponsor to actively 
monitor proposed investigations so that appropriate public disclosure 
can occur and so that other IRB's, investigators, and FDA are notified 
of an IRB determination that it cannot approve the investigation. FDA 
is proposing to amend 814.9(d) (21 CFR 814.9(d)) to codify the need for 
sponsors to identify information publicly disclosed consistent with the 
requirements of Sec. 50.24(a)(5)(ii) and (a)(5)(iii).

XV. References

    The following information has been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Prentice, E. D., et al., ``IRB Review of a Phase II 
Randomized Clinical Trial Involving Incompetent Patients Suffering 
from Severe Closed Head Injury,'' IRB A Review of Human Subjects 
Research, 15:1-7, 1993.
    2. Prentice, E. D., et al., ``An Update on the PEG-SOD Study 
Involving Incompetent Subjects: FDA Permits an Exception to Informed 
Consent Requirements,'' IRB A Review of Human Subjects Research, 
16:16-18, 1994.
    3. Fost N., and J. A. Robertson, ``Deferring Consent with 
Incompetent Patients in an Intensive Care Unit.'' IRB Review of 
Human Subjects Research, 2:5-6, 1980.
    4. Beauchamp, T. L., ``Commentary: The Ambiguities of `Deferred 
Consent','' IRB Review of Human Subjects Research, 2:6-9, 1980.
    5. Levine, R. J., ``Commentary: Deferred Consent,'' Controlled 
Clinical Trials, 12:546-550, 1991.
    6. Olson, C. M., ``Editorial: The Letter or the Spirit; Consent 
for Research in CPR,'' Journal of the American Medical Association, 
271:1445-1447, 1994.
    7. Abramson, N. S., and P. Safar, ``Deferred Consent: Use in 
Clinical Resuscitation Research,'' Annals of Emergency Medicine, 
19:781-784, 1990.
    8. ``Informed Consent--Legally Effective and Prospectively 
Obtained,'' OPRR Reports-Human Subject Protections, Number 93-3, 
1993.
    9. Jane, J. A., June 28, 1993, letter to D. A. Kessler and 
September 14, 1993, response.
    10. Herr, D. L., July 23, 1993, letter to D. A. Kessler and 
September 14, 1993, response.
    11. Binder, L. S., and M. H. Biros, July 23, 1993, letter to D. 
A. Kessler and September 14, 1993, response.
    12. Zitnay, G. A., June 22, 1993, letter to D. A. Kessler and 
September 14, 1993, response.
    13. Abramson, N. S., and P. Safar, ``Response to Commentary,'' 
Controlled Clinical Trials, 12:551-552, 1991.
    14. Parrillo, J. E., ``Special Article: Research in critical 
care medicine: Present status of critical care investigation,'' 
Critical Care Medicine, 19:569-577, 1991.
    15. Halperin, H. R., et al., ``A Preliminary Study of 
Cardiopulmonary Resuscitation by Circumferential Compression of the 
Chest with Use of a Pneumatic Vest,'' New England Journal of 
Medicine, 329:762-768, 1993.
    16. Cohen, T. J., et al., ``A Comparison of Active Compression-
Decompression Cardiopulmonary Resuscitation with Standard 
Cardiopulmonary Resuscitation for Cardiac Arrests Occurring in the 
Hospital,'' New England Journal of Medicine, 329:1918-1921, 1993.

[[Page 49100]]

    17. Lurie, K. G., et al., ``Evaluation of Active Compression-
Decompression CPR in Victims of Out-of-Hospital Cardiac Arrest,'' 
Journal of the American Medical Association, 271:1405-1411, 1994.
    18. Schwab, T. M., ``A Randomized Clinical Trial of Active 
Compression-Decompression CPR vs Standard CPR in Out-of-Hospital 
Cardiac Arrest in Two Cities,'' Journal of the American Medical 
Association,273:1261-1268, 1995.
    19. Olson, C. M., ``Editorial: Plungers and Polemics: Active 
Compression-Decompression CPR and Federal Policy,'' Journal of the 
American Medical Association, 273:1299-1300, 1995.
    20. Levine, R. J., ``Editorial: Research in Emergency 
Situations; The Role of Deferred Consent,'' Journal of the American 
Medical Association, 273:1300-1302, 1995.
    21. Marwick, C., ``Research in Emergency Circumstances,'' 
Journal of the American Medical Association, 273:687-688, 1995.
    22. ``Informed Consent in Emergency Research,'' Consensus from 
the Coalition Conference of Acute Resuscitation and Critical Care 
Researchers, 1994.
    23. ``Public Forum on Informed Consent in Clinical Research 
Conducted in Emergency Circumstances,'' transcript of January 9, 
1995.
    24. ``Public Forum on Informed Consent in Clinical Research 
Conducted in Emergency Circumstances,'' transcript of January 10, 
1995.
    25. ``Report of the Public Forum on Informed Consent in Clinical 
Research Conducted in Emergency Circumstances,'' FDA and NIH, May 
1995.
    26. ``Problems in Securing Informed Consent of Subjects in 
Experimental trials of Unapproved Drugs and Devices,'' Hearing 
before the Subcommittee on Regulation, Business Opportunities, and 
Technology of the Committee on Small Business, House of 
Representatives, Washington, DC, Serial No. 103-85, 1994.
    27. Miller, B. L., ``Philosophical, ethical, and legal aspects 
of resuscitation medicine,'' Critical Care Medicine, 16:1059-1062, 
1988.
    28. Miller, B. L., ``The Ethics of Cardiac Arrest Research,'' 
Annals of Emergency Medicine, 22-118-124, 1993.
    29. ``Waiver of Informed Consent: A Critical Issue for Improving 
Treatment of Emergent Medical Conditions,'' North American Society 
of Pacing and Electrophysiology Government Relations Committee 
Position Statement, Testimony presented at FDA/NIH Public Forum, 
1995.
    30. Wears, R. L., Written testimony presented at FDA/NIH Public 
Forum, 1995.
    31. McCarthy, C. R., ``To Be or Not to Be: Waiving Informed 
Consent in Emergency Research,'' Kennedy Institute of Ethics 
Journal, 5:155-162, 1995.
    32. ``Implementing Human Research Regulations; Second Biennial 
Report on the Adequacy and Uniformity of Federal Rules and Policies, 
and of their Implementation, for the Protection of Human Subjects,'' 
President's Commission for the Study of Ethical Problems in Medicine 
and Biomedical and Behavioral Research, 1983.
    33. Fost, N. C., ``Part 3; Human Subjects in Cardiopulmonary 
Resuscitation Research,'' in ``Ethics in Emergency Medicine,'' 
Edited by Iserson, K. V., et al., Williams & Wilkins, Baltimore, pp. 
77-81, 1986.
    34. Sprung, C. L., and B. J. Winick, ``Informed Consent in 
Theory and Practice: Legal and Medical Perspectives on the Informed 
Consent Doctrine and a Proposed Reconceptualization,'' Critical Care 
Medicine, 17:1346-1354, 1989.

List of Subjects

21 CFR Part 50

    Informed consent, Prisoners, Reporting and recordkeeping 
requirements, Research, 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.

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, it is 
proposed that 21 CFR parts 50, 56, 312, 314, 601, 812, and 814 be 
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 members means the following legally competent persons: 
Spouses; parents; children (including adopted children); brothers, 
sisters and their spouses; 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 be 
obtained if the IRB (with a concurring licensed physician member or 
consultant) 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 trials, is necessary to determine 
what particular intervention is most beneficial.
    (2) Obtaining informed consent is not feasible because:
    (i) The subjects will not be able to give consent as a result of 
their medical condition; and
    (ii) The intervention under study must be administered before 
consent from legally authorized representatives is feasible; and
    (iii) There is no reasonable way to identify prospectively the 
individuals likely to become eligible for the research because the 
emergence of the condition to be studied cannot be predicted reliably 
in particular individuals.
    (3) The opportunity for the subjects to participate in the research 
is in the interest of the subjects because:
    (i) A life-threatening situation necessitates intervention, and
    (ii) The risk of the investigation is reasonable in light of what 
is known about the medical condition and the risks and benefits of 
current therapy, if any, and what is known about the risks and benefits 
of the proposed intervention or activity.
    (4) The research could not practicably be carried out without the 
waiver.
    (5) Additional protections of the rights and welfare of the 
subjects will be provided, including, at least:
    (i) Consultation (which may include consultation carried out by the 
IRB itself) with representatives of the 

[[Page 49101]]
communities from which the subjects will be drawn;
    (ii) Public disclosure prior to the commencement of the study 
sufficient to describe the study and its risks and benefits;
    (iii) Public disclosure of sufficient information following 
completion of the study to apprise the community and researchers of the 
study and its results; and
    (iv) The establishment of an independent data and safety monitoring 
board.
    (6) The IRB has reviewed and approved an informed consent document 
for use with subjects or legal representatives in situations in which 
obtaining such consent may be feasible for some subjects.
    (b) When possible and at the earliest possible 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) will be informed of the 
subject's inclusion in the research study, the details of the research 
study, and that 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) may 
discontinue the subject's participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
    (c) The IRB determinations required by paragraph (a) of this 
section and the documentation required by paragraphs (d) and (e) of 
this section are to be retained by the IRB for at least 3 years after 
completion of the research, and the records shall be accessible for 
inspection and copying by FDA in accordance with 56.115(b) of this 
chapter.
    (d) Protocols involving an exception to the informed consent 
requirement under this section must be performed under an 
investigational new drug application (IND) or investigational device 
exemption (IDE). FDA requires clear identification of protocols that 
would include subjects who are unable to consent, and submission of 
those protocols in a separate IND/IDE (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 supplemental 
applications under Secs. 312.30 or 812.35 of this chapter.
    (e) If an IRB determines that it cannot approve this research 
because the research 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 in writing to the sponsor of the research. The 
sponsor of the research must share this information with FDA, 
researchers/clinical investigators who are asked to participate in this 
or a substantially equivalent trial, and to other IRB's which are asked 
to review this or a substantially equivalent clinical trial.

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 a new sentence 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, the IRB 
may required the investigator to provide subjects with a written 
statement regarding the research.
    (e) * * * For studies involving an exception to informed consent 
under Sec. 50.24 of this chapter, an IRB shall 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.
* * * * *
    (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)(5)(ii) and (a)(5)(iii). The IRB shall provide this 
information to the sponsor promptly so that the sponsor is aware that 
such disclosure has occurred. The sponsor shall provide copies of the 
information disclosed to FDA.

    6. Section 56.111 is amended by adding new paragraph (c) to read as 
follows:


Sec. 56.111  Criteria for IRB approval of research.

* * * * *
    (c) When the research involves an exception from informed consent 
for emergency research under Sec. 50.24 of this chapter, the IRB finds 
and documents that the safeguards set forth in Sec. 50.24 are included.

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

    7. 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).

    8. Section 312.2 is amended by adding pragraph (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.
* * * * *
    9. Section 312.20 is amended by adding paragraph (c) to read as 
follows:


Sec. 312.20  Requirements 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.
    10. Section 312.23 is amended by adding paragraph (f) to read as 
follows:

Sec. 312.23   IND content and format.

* * * * *
    (f) If the investigation involves an exception from informed 
consent under Sec. 50.24 of this chapter, prominent 

[[Page 49102]]
identification on the cover sheet that the investigation is subject to 
the requirements in Sec. 50.24.
    11. Section 312.30 is amended by adding a new sentence to the end 
of the introductory text to read as follows:

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.
* * * * *
    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 proposed 
investigations involving an exception from informed consent under 
Sec. 50.24 of this chapter. The sponsor shall determine when the public 
disclosures required by Sec. 50.24(a)(5)(ii) and (a)(5)(iii) of this 
chapter of the proposed investigation have occurred and promptly shall 
submit to the IND file and to Dockets Management Branch copies of the 
information that was disclosed.
    (b) The sponsor also shall monitor such proposed 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 trial, and other IRB's that are asked to review this or a 
substantially equivalent trial.

    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 
Sec. 50.23 or Sec. 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.

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

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

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 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).

    15. Section 314.430 is amended by adding two sentences to the end 
of paragraph (d) to read as follows:

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

* * * * *
    (d)* * * For applications concerning investigations 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) to the 
IND file and to Dockets Management Branch. Copies of this information 
will be available to the public from the Dockets Management Branch.
* * * * *

PART 601--LICENSING

    16. 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, 372, 
374, 379e, 381); secs. 215, 301, 351 of the Public Health Service 
Act (42 U.S.C. 216, 241, 262, 263).

    17. Section 601.51 is amended by adding two sentences to the end of 
paragraph (d) to read as follows:


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

* * * * *
    (d) * * * For applications concerning investigations 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) to the 
IND file and to the Dockets Management Branch. Copies of this 
information will be available to the public from the Dockets Management 
Branch.
* * * * *

PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS

    18. 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).

    19. Section 812.20 is amended by revising paragraph (a)(1) and 
adding 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 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, and
    (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.

* * * * *
    20. Section 812.35 is amended by adding a 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 two sentences to the end of 
paragraph (b)(2) to read as follows:

Sec. 812.38   Confidentiality of data and information.

* * * * *
    (b) * * *
    (2) * * * If a device is subject to an investigation that involves 
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) to the 
IDE file and to the Dockets Management Branch. Copies of this 
information will be available to the public from the Dockets Management 
Branch.

* * * * *
    22. New section 812.47 is added to subpart C to read as follows:

[[Page 49103]]



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

    (a) The sponsor shall monitor the progress of all proposed 
investigations involving an exception from informed consent under 
Sec. 50.24 of this chapter. The sponsor shall determine when the public 
disclosures under Sec. 50.24(a)(5)(ii) and (a)(5)(iii) of this chapter 
of the proposed investigation have occurred. The sponsor promptly shall 
submit copies of the information that has been publicly disclosed to 
the IDE file and also to the Dockets Management Branch.
    (b) The sponsor also shall monitor such studies 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 trial, and 
other IRB's that are asked to review this or a substantially equivalent 
trial.

PART 814--PREMARKET APPROVAL OF MEDICAL DEVICES

    23. The authority citation for 21 CFR part 814 continues 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 adding two sentences to the end of 
paragraph (d) to read as follows:


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

* * * * *
    (d)* * * For applications concerning investigations involving an 
exception from informed consent under Sec. 50.24 of this chapter, 
sponsors are required to submit copies of information publicly 
disclosed under Sec. 50.24(a)(5)(ii) and (a)(5)(iii) to the IDE file 
and to the Dockets Management Branch. Copies of this information will 
be available to the public from the Dockets Management Branch.
* * * * *

    Dated: August 31, 1995.
David A. Kessler,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 95-23239 Filed 9-20-94; 8:45 am]
BILLING CODE 4160-01-F