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Regulatory Information

Exception from Informed Consent for Studies Conducted in

Emergency Settings: Regulatory Language and Excerpts from

Preamble - Information Sheet

Information Sheet - Guidance for Institutional Review Boards and Clinical

Investigators (Exception from Informed Consent for Studies Conducted in

Emergency Settings: Regulatory Language and Excerpts from Preamble)

The federal regulations for the protection of human subjects in research require informed

consent, with a few narrow exceptions. Following industry-FDA meetings (1993); a

Congressional hearing (May 1994); a Coalition-conference of academic, medical and

research organizations (October 1994); and an FDA-sponsored public forum (January

1995), FDA published in the Federal Register in September 1995, [60 FR 49086] a

proposal to amend its regulations to permit a limited class of research in emergency

settings without consent. Following a careful review of the comments received on the

proposal, a final regulation was published in the Federal Register on October 2, 1996,

[61 FR 51498]. The Department of Health and Human Services published, in the same

issue, its waiver criteria which match the FDA requirements [61 FR 51531]. These

documents establish a single standard for this class of research.

The new FDA regulation (21 CFR 50.24) provides a narrow exception to the requirement

for informed consent from each human subject, or his or her legally authorized

representative, prior to initiation of an experimental intervention. The exception would

apply to a limited class of research activities involving human subjects who are in need

of emergency medical intervention but who cannot give informed consent because of

their life-threatening medical condition, and who do not have a legally authorized person

to represent them. The intent of the new regulation is to allow research on lifethreatening conditions for which available treatments are unproven or unsatisfactory and

where it is not possible to obtain informed consent, while establishing additional

protections to provide for safe and ethical studies.

FDA recognizes that persons with life-threatening conditions who can neither give

informed consent nor refuse enrollment are a vulnerable population. FDA recognizes that

the lack of autonomy and inability of subjects to give informed consent requires

additional protective procedures in the review, approval, and operation of this research.

The exception from the informed consent requirement permitted by the rule is

conditional upon documented findings by an Institutional Review Board (IRB).
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The regulation specifically requires the concurrence of a licensed physician "who is a

member of or consultant to the IRB and who is not otherwise participating in the clinical

investigation" (Sec. 50.24(a)). This requirement is similar to 21 CFR 50.23 which

requires an independent assessment by a physician not otherwise participating in the

research when an investigational product is to be used in a life-threatening situation.

Because 21 CFR 50.24 permits an exception from the requirement for informed consent

for a group of subjects, the case-by-case independent determination is replaced by the

general concurrence of a licensed physician. The option for use of a consultant to the IRB

is to provide flexibility, for example, when the physician member(s) cannot participate in

the deliberation and voting due to conflict of interest. Because the documented

concurrence of the physician is required for approval of these studies, IRBs should

ensure that meeting minutes specifically record this affirmative vote.

[Note: The numbering system used below follows the regulation numbers. The regulatory

language is in italics. Readers are referred to the full text of the regulation and the

preamble for additional guidance.]

According to 21 CFR 50.24, the IRB must find and document each of the following. It is

clear from the regulations's wording that it is the IRB's responsibility to make decisions

as to whether the criteria of the rule are met.

50.24(a)(1) The human subjects are in a life-threatening situation,

The criteria contained in the rule do not require the condition to be

immediately life-threatening or to immediately result in death. Rather, the

subjects must be in a life-threatening situation requiring intervention before

consent from a legally authorized representative is feasible. Life-threatening

includes diseases or conditions where the likelihood of death is high unless the

course of the disease or condition is interrupted. (See Sec. 312.81.) People

with the conditions cited in the examples provided in the comments--e.g.,

long-term or permanent coma, stroke, and head injury--may survive for long

periods but the likelihood of survival is not known during the therapeutic

window of treatment. People with these conditions are clearly at increased risk

of death due to infection, pulmonary embolism, progression of disease, etc.

The rule would apply in such situations if the intervention must be given before

consent is feasible in order to be successful. The informed consent waiver

provision is not intended to apply to persons who are not in an emergent

situation, e.g., individuals who have been in a coma for a long period of time

and for whom the research intervention should await the availability of a legally

authorized representative of the subject.

available treatments are unproven or unsatisfactory, and

"Clinical equipoise" must exist. "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." (60 FR 49086 at

49093, September 21, 1995.)

the collection of valid scientific evidence, which may include evidence obtained through

randomized placebo-controlled investigations, is necessary to determine the safety and

effectiveness of particular interventions.
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Although the regulation specifically references placebo controlled trials, this

was done to indicate that such trials may be conducted when appropriate.

Other controls, e.g, active controls and historical controls, may also be used

when they are appropriate and adequate to the task of providing evidence that

the drug or device will have the effect claimed. In virtually all cases, when a

placebo is used, standard care, if any, would be given to all subjects, with

subjects randomized to receive, in addition, the test treatment or a placebo. An

exception to this would be the situation in which the test is to determine

whether standard treatment is in fact useful. In that case, there must be a

group that does not receive it.

(2) Obtaining informed consent is not feasible because:

(i) the subjects will not be able to give their informed consent as a result of their medical

condition;

Subjects do not have to be comatose, but the medical condition under study

must prevent obtaining valid informed consent. The agency expects the IRB to

determine, based on the specific details of the individual clinical investigation

(including the window of opportunity for treatment), the procedures the

investigator must follow to attempt to obtain informed consent before enrolling

a subject in an investigation without such consent. IRBs also should be

knowledgeable about an institution's procedures regarding the use of advance

medical directives and assess whether the proposed clinical investigation is

consistent with those procedures.

(ii) the intervention under investigation must be administered before consent from the

subjects' legally authorized representatives is feasible; and

The agency expects the IRB to determine, based on the specific details of the

individual clinical investigation (including the window of opportunity for

treatment), the procedures the investigator must follow to attempt to obtain

informed consent before enrolling a subject in an investigation without such

consent.

(iii) There is no reasonable way to identify prospectively the individuals likely to become

eligible for participation in the clinical investigation.

If an IRB determines that it is not appropriate to waive the requirement for

informed consent because there is a reasonable way to identify prospectively

the individuals likely to become eligible for the study, then this exception would

not apply. In that case, only those subjects with the condition who gave prior

consent may be enrolled in the study. Those individuals who either did not

make a decision or who refused participation would be excluded from

participation in the study. While an exception would not be allowed under this

rule, the individual exception allowed under 21 CFR 50.23 might be applicable

in some circumstances.

(3) Participation in the research holds out the prospect of direct benefit to the subjects

because:

(i) subjects are facing a life-threatening situation that necessitates intervention;
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(ii) appropriate animal and other preclinical studies have been conducted, and the

information derived from those studies and related evidence support the potential for the

intervention to provide a direct benefit to the individual subjects; and

(iii) risks associated with the investigation are reasonable in relation to what is known

about the medical condition of the potential class of subjects, the risks and benefits of

standard therapy, if any, and what is known about the risks and benefits of the proposed

intervention or activity.

(4) The clinical investigation could not practicably be carried out without the waiver.

If scientifically sound research can be practicably carried out using only

consenting subjects (directly, or in most cases for the research contemplated in

the rule, with legally authorized representatives), then the agency thinks it

should be carried out without involving nonconsenting subjects. By practicable,

the agency means, for example, (1) that recruitment of consenting subjects

does not bias the science and the science is no less rigorous as a result of

restricting it to consenting subjects; or (2) that the research is not unduly

delayed by restricting it to consenting subjects.

(5) The proposed investigational plan defines the length of the potential therapeutic

window based on scientific evidence, and the investigator has committed to attempting

to contact a legally authorized representative for each subject within that window of time

and, if feasible, to asking the legally authorized representative contacted for consent

within that window rather than proceeding without consent. The investigator will

summarize efforts made to contact legally authorized representatives and make this

information available to the IRB at the time of continuing review.

The agency believes that these procedures will ensure that appropriate efforts

are made by the investigator to obtain consent from subjects prior to

enrollment. The agency expects these procedures to be documented in the

protocol and/or by the IRB, and the efforts made by investigators to be

documented in the material presented to the IRB for its continuing review.

(6) The IRB has reviewed and approved informed consent procedures and an informed

consent document consistent with Sec. 50.25. These procedures and the informed

consent document are to be used with subjects or their legally authorized

representatives in situations where use of such procedures and documents is feasible.

The IRB has reviewed and approved procedures and information to be used when

providing an opportunity for a family member to object to a subject's participation in the

clinical investigation consistent with paragraph (a)(7)(v) of this section.

IRBs need to be aware of state and local laws. Some states have laws which

prohibit entry of subjects into research without their express consent. This new

rule does not preempt state/or local law.

The agency has specifically included family members under this rule because

the opportunity for an available family member to object to a potential

subject's participation in such a clinical investigation provides an additional and

an important protection to these individuals. Otherwise, if consent from a

subject or the subject's legally authorized representative were not feasible, the

eligible individual could be enrolled into the investigation. Thus, by permitting a
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family member (even one who is not a legally authorized representative) to

object to an individual's inclusion in the investigation, a further protection is

provided to that individual. A family member must be provided an opportunity

to object to the potential subject's participation, if feasible within the

therapeutic window, when obtaining informed consent from the subject is not

feasible and a legally authorized representative is not available. The agency

recognizes that this may not constitute legally effective informed consent if the

family member is not a legally authorized representative under State law. FDA

is not establishing a hierarchy of family members although an IRB may

consider the need for creating a hierarchy in reviewing individual

investigations. Under this rule only one family member would need to be

consulted and agree or object to the patient's participation in the research. If

family members were to disagree, the researcher and family members would

need to work out the disagreement.

(7) Additional protections of the rights and welfare of subjects will be provided, including,

at least:

(i) consultation (including, where appropriate, consultation carried out by the IRB) with

representatives of the communities in which the clinical investigation will be conducted

and from which the subjects will be drawn

While an IRB may appropriately decide to supplement its members with

consultants from the community, broader consultation with the community is

needed for this type of research. The agency expects the IRB to provide an

opportunity for the community from which research subjects may be drawn to

understand the proposed clinical investigation and its risks and benefits and to

discuss the investigation. The IRB should consider this community discussion in

reviewing the investigation. Based on this community consultation, the IRB

may decide, among other things, that it is appropriate to attempt to exclude

certain groups from participation in the investigation, or that wider community

consultation and discussion is needed. As described in the preamble to the

proposed rule (60 FR 49086, September 21, 1995), IRBs should consider, for

example, having a public meeting in the community to discuss the protocol;

establishing a separate panel of members of the community from which the

subjects will be drawn; including consultants to the IRB from the community

from which the subjects will be drawn; enhancing the membership of the IRB

by adding members who are not affiliated with the institution and are

representative of the community; or developing other mechanisms to ensure

community involvement and input into the IRB's decisionmaking process. It is

likely that multiple methods may be needed in order to provide the

supplemental information that the IRB will need from the community to review

this research.

(ii) Public disclosure to the communities in which the clinical investigation will be

conducted and from which the subjects will be drawn, prior to initiation of the clinical

investigation, of plans for the investigation and its risks and expected benefits;

It is the IRB's responsibility to determine the information to be disclosed. This

information could include, but may not necessarily be limited to, the

information that is found in the informed consent document, the investigator's

brochure, and the research protocol. The IRB should consider how best to

publicly disclose, prior to commencement of the clinical investigation, sufficient
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information to describe the investigation's risks and benefits, e.g., relevant

information from the investigator's brochure, the informed consent document,

and the investigational protocol. Initial disclosure of information will occur

during the community consultation process. Disclosure of this information to

the community will inform individuals within the community about the clinical

investigation and permit them to raise concerns and objections.

(iii) Public disclosure of sufficient information following completion of the clinical

investigation to apprise the community and researchers of the study, including the

demographic characteristics of the research population, and its results;

It is necessary to provide comprehensive summary data from the completed

trial to the research community in order to permit other researchers to assess

the results of the clinical investigation. The agency thinks that there must be a

scientific need to conduct clinical investigations involving subjects who are

unable to consent; if previous investigations have already provided the

scientific answer, this should be shared broadly with the research community.

Sufficient information may be contained in a scientific publication of the results

of the completed investigation; in other instances, a publication may need to

be supplemented by additional information. The agency has modified Sec.

50.24(a)(7)(iii) to clarify that the information to be disclosed is to include the

demographic characteristics (age, gender, and race) of the research population.

For a multicenter investigation, the agency anticipates that the sponsor and/or

lead investigators will be responsible for analyzing the results of the overall

investigation, including the demographic characteristics of the research

population, and that these results will be published (or reported in the lay

press) within a reasonable period of time following completion of the

investigation. Publication in a scientific journal or reports of the results by lay

press, that would be supplemented upon request by comprehensive summary

data, will enable the research community, e.g., researchers not connected to

the clinical investigation, to learn of the research's results. Following

publication, the IRB will be responsible for determining appropriate

mechanisms for providing this information, possibly supplemented by a lay

description, to the community from which research subjects were drawn. The

usual rules of marketing and promotion apply to the disclosure of this

information. The agency notes that it is common for the results of research to

be reported in the lay press and published in peer reviewed journals.

(iv) Establishment of an independent data monitoring committee to exercise oversight of

the clinical investigation; and

A data monitoring committee will help ensure that if it becomes clear that the

benefits of the investigational intervention are established, or that risks are

greater than anticipated, or that the benefits do not justify the risks of the

research, the investigation can be modified to minimize those risks or the

clinical investigation can be halted. The data monitoring committee is

established by the sponsor of the research, as an advisory body to the sponsor.

An independent committee is constituted of individuals not otherwise

connected with the particular clinical investigation. A variety of expertise is

required for an effective data monitoring committee. Typically included are

clinicians specializing in the relevant medical field(s), biostatisticians, and

bioethicists. The data monitoring committee receives study data on an ongoing
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basis on a schedule generally defined in the investigational protocol; based on

its review of the data it may recommend to the sponsor that the clinical

investigation be modified or stopped. In effect, it is responsible for making sure

that continuing the investigation in its current format remains appropriate, on

both safety and scientific grounds. A number of reasonable models for

establishment and function of these committees are described and discussed in

S. Ellenberg, N. Geller, R. Simon, S. Yusuf (editors), Practical issues in data

monitoring of clinical trials (Proceeding of an International Workshop) Statistics

in Medicine, vol. 12; 1993. If a sponsor accepts a data monitoring committee's

recommendation to stop the investigation or to institute a major modification

of the trial, the sponsor is required to notify FDA and all participating

investigators and IRBs in a written IND or IDE safety report within 10 working

days after the sponsor's initial receipt of the information. (See Secs. 312.32,

312.56(d), and 812.150(b)(1)).

If an IRB, a subcommittee of the IRB, or some other preexisting institutional committee

were to serve as a data monitoring committee, it would need to be constituted as a data

monitoring committee when it functions in that capacity. The agency thinks that the

duties and scope of activities of an IRB and a data monitoring committee are quite

different and that it is important for separate entities to be established. The agency

would not object, however, to an already established committee, such as an IRB, serving

as a data monitoring committee as long as that committee was constituted to perform

the duties of a data monitoring committee and operated as such separately and distinctly

from its IRB activities.

(v) If obtaining informed consent is not feasible and a legally authorized representative is

not reasonably available, the investigator has committed, if feasible, to attempting to

contact within the therapeutic window the subject's family member who is not a legally

authorized representative, and asking whether he or she objects to the subject's

participation in the clinical investigation. The investigator will summarize efforts made to

contact family members and make this information available to the IRB at the time of

continuing review.

See previous explanation under Sec. 50.24(a)(6).

(b) The IRB is responsible for ensuring that procedures are in place to inform, at the

earliest feasible opportunity, each subject, or if the subject remains incapacitated, a

legally authorized representative of the subject, or if such a representative is not

reasonably available, a family member, of the subject's inclusion in the clinical

investigation, the details of the investigation and other information contained in the

informed consent document. The IRB shall also ensure that there is a procedure to

inform the subject, or if the subject remains incapacitated, a legally authorized

representative of the subject, or if such a representative is not reasonably available, a

family member, that he or she may discontinue the subject's participation at any time

without penalty or loss of benefits to which the subject is otherwise entitled. If a legally

authorized representative or family member is told about the clinical investigation and

the subject's condition improves, the subject is also to be informed as soon as feasible. If

a subject is entered into a clinical investigation with waived consent and the subject dies

before a legally authorized representative or family member can be contacted,

information about the clinical investigation is to be provided to the subject's legally

authorized representative or family member, if feasible.
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The agency thinks that it may not always be possible to develop a meaningful

informed consent document for continued participation in the research,

because the relevant information may vary significantly depending upon when

it becomes feasible to provide the information to the subject or legally

authorized representative.

It is up to the IRB to determine whether it is possible or desirable, given the

nature of the clinical investigation, to have an actual document that could be

signed for continued participation in the investigation. The agency notes that

such a document, that would be signed after entry into an investigation, would

not constitute consent for what had already occurred; it could, however, serve

to document that the subject consented to continued participation in the

investigation. The agency notes that Secs. 312.60 and 812.140 require the

clinical investigator to document data pertinent to each individual in the

investigation. This documentation should include information that the subject,

legally authorized representative, or family member was informed of the

subject's inclusion in the clinical investigation, the details of the investigation,

and other information contained in the informed consent document.

Like other IRB records, records of the determinations above must be kept for a

minimum of three years after the completion of the clinical investigation (21

CFR 50.24(c)). Again, like other IRB records, these are subject to inspection

and copying by FDA.

(d) Protocols involving an exception to the informed consent requirement under this

section must be performed under a separate investigational new drug application (IND)

or investigational device exemption (IDE) that clearly identifies such protocols as

protocols that may include subjects who are unable to consent. The submission of those

protocols in a separate IND/IDE is required even if an IND for the same drug product or

an IDE for the same device already exists. Applications for investigations under this

section may not be submitted as amendments under Secs. 312.30 or 812.35 of this

chapter.

The submission of a separate IND or IDE will ensure that FDA reviews the

application before the study may proceed. FDA review of the application will

enable the agency to assess whether the available treatments for the condition

are unproven or unsatisfactory, whether the intervention is reasonable,

whether the study design will provide the information sought, and whether

other conditions of the regulations are met. The amount of information needed

in the application will differ depending upon the particular intervention. If an

IND or IDE exists, the separate application does not need to duplicate, and the

sponsor does not need to resubmit, information that is contained in the

existing IND or IDE; the separate application will need to reference the existing

IND or IDE, contain a protocol for the clinical investigation that includes a

description of how the investigation proposes to meet the conditions of this

regulation, and contain only the study-specific information required by Secs.

312.23, 812.20, and 812.25, as appropriate.

If the investigation involves a product that has received marketing approval

and the use is within the product's approved labeling, and without dosage or

schedule change if for a drug product, the protocol may simply need to be

accompanied by the product's approved labeling and a description of how the

investigation proposes to meet the conditions of this regulation; no toxicology

or manufacturing controls or chemistry information may need to be submitted.
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By submitting this information to the agency for review, the dual review by

both FDA and an IRB will provide additional protections to the subjects of this

research.

If the clinical investigation involves a product that has received marketing

approval, but involves a route of administration or dosage level or use in a

subject population or other factor that significantly increases the risks (or

decreases the acceptability of the risks) associated with the use of the product,

or if the investigation involves an investigational product for which an IND or

IDE does not exist, then the IND or IDE would need to include information to

support the altered conditions of use, including toxicology, chemistry, and

clinical information, as appropriate.

(e) If an IRB determines that it cannot approve a clinical investigation because the

investigation does not meet the criteria in the exception provided under paragraph (a) of

this section or because of other relevant ethical concerns, the IRB must document its

findings and provide these findings promptly in writing to the clinical investigator and to

the sponsor of the clinical investigation. The sponsor of the clinical investigation must

promptly disclose this information to FDA and to the sponsor's clinical investigators who

are participating or are asked to participate in this or a substantially equivalent clinical

investigation of the sponsor, and to other IRBs that have been, or are, asked to review

this or a substantially equivalent investigation by that sponsor.

By "substantially equivalent" the agency means other clinical investigations

that propose to invoke this exception from informed consent and that involve

basically the same medical conditions and investigational treatments. The

agency intends this requirement to refer to clinical investigations conducted by

the same sponsor.

It is the sponsor's responsibility to determine that a study is "substantially equivalent." If

a protocol invoking this exception is modified by the sponsor in order to respond to IRB

concerns that it does not meet the criteria in Sec. 50.24(a) of the exception or because

of other relevant ethical concerns, and it is a multicenter study, then the IRB's written

findings are to be disclosed to other centers that either are, or may be, participating in

the study. If there is a change in a protocol in a multicenter trial, there is re-review of

the protocol by all the IRBs of the institutions participating in the multicenter trial. If the

change is minor, it may be eligible for expedited review under Sec. 56.110, which

permits the IRB to use an expedited review procedure to review minor changes in

previously approved research during the period for which approval is authorized. If the

change is significant, it would need to be reviewed by the full committee. It is the

sponsor's responsibility to determine if it has a substantially similar protocol

necessitating information dissemination.