[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]]
_______________________________________________________________________
Part III
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
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
