Protection of Human Subjects; Informed Consent

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