OBJECTIVE:

To assist investigators in planning protocols and meeting the requirements for research that is planned for life-threatening emergency situations, including the requirements that must be met for waiver of informed consent in these situations.

DESCRIPTION:

A.  Emergency Setting Research The term “Emergency Setting Research” refers to human subjects research designed to test medical interventions that occur in situations where potentially lifesaving interventions are utilized.

The VCU IRB will accept applications for research planned for emergency settings using the VCU IRB application and processes for initial review; however, prior consultation with the ORSP is strongly recommended.

The following two (2) documents provide guidance relative to planned research in the emergency setting: 

1)  The 1998 Update FDA information sheet "Exception from Informed Consent for Studies Conducted in Emergency Settings: Regulatory Language and Excerpts from Preamble," which is a compilation of the wording of 21 CFR 50.24 and pertinent portions of the preamble from the October 2, 1996 Federal Register.  As per the FDA Information Sheet, 21 CFR 50.24 specifies regulatory requirements regarding the waiver of prospective informed consent for the conduct of FDA-regulated planned research in life-threatening emergent situations.

2) The 1996 OPRR (now, OHRP) Report titled “Informed Consent Requirements in Emergency Research.  Herein, a waiver of the applicability of the 45CFR 46 requirement for obtaining and documenting informed consent involving research activities that may be carried out in human subjects who are in need of emergency therapy and for whom, because of the subjects’ medical condition and the unavailability of LARs of the subjects, no legally effective informed consent can be obtained.  

B.  Prospective IRB Approval of Emergency ‘Setting’ Research:

The VCU IRB may consider an “Emergency Research Consent Waiver” for research, which meets the following strictly limited conditions detailed under EITHER (1) or (2).  Note that there are many similarities between the two sets of regulations.  Research subject to FDA regulations requires additional IRB reponsibilities in ensuring specific IND or IDE approvals as well as, reporting IRB disapprovals to sponsors.  OECO will work with the IRB to facilitate the sponsor report. Emergency setting research with waiver of informed consent that is not subject to FDA regulations, requires a report to OHRP indicating that the IRB found the conditions in A2 below to be met OECO will work with the IRB to facilitate the reporting.of these findings to OHRP and before the research is approved by the IRB to begin.

1.      Research Subject to FDA Regulations (Subject to 21CFR 50.24):

Guidance from 1998 FDA Information Sheet:

“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 life-threatening 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).

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.”

IRB Responsibilities at 21CFR 50.24(b), (c), (d), and (e)

See the FDA Information Sheet referenced above for more info regarding each of the elements above.

OR

2.      Research not subject to FDA regulations (that is, not employing an investigational drug, device, or biologic in a planned emergency setting):

The information below comes from the 1996 OPRR guidance document referenced above.  The IRB must determine the specific findings below:

“The IRB responsible for the review, approval, and continuing review of the research has approved both the research and a waiver of informed consent and has (1) found and documented that the research is not subject to FDA regulations and (2) found and documented and reported to OHRP that the following conditions have been met relative to the research:

a)      The human subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence, which may include evidence obtained through randomized placebo-controlled investigations, is necessary to determine the safety and effectiveness of particular interventions.

b)      Obtaining informed consent is not feasible because: i) the subjects will not be able to give their informed consent as a result of their medical condition, ii) the intervention under investigation must be administered before consent from the subjects' legally authorized representatives is feasible, and iii) there is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the research.

c)      Participation in the research holds out the prospect of direct benefit to the subjects because i) subjects are facing a life-threatening situation that necessitates intervention. ii) Appropriate animal and other preclinical studies have been conducted and the information derived from those studies and related evidence support the potential for the intervention to provide a direct benefit to the individual subjects, and iii) risks associated with the investigation are reasonable in relation to what is known about the medical condition of the potential class of subjects, the risks and benefits of standard therapy, if any, and what is known about the risks and benefits of the proposed intervention or activity.

d)      The research could not practicably be carried out without the waiver.

e)      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.

f)       The IRB has reviewed and approved informed consent procedures and an informed consent document.  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.

g)      Additional protections of the rights and welfare of the subjects will be provided, including, at least: i) consultation (including, where appropriate, consultation carried out by the IRB) with representatives of the communities in which the research will be conducted and from which the subjects will be drawn, ii) public disclosure to the communities in which the research will be conducted and from which the subjects will be drawn, prior to initiation of the research, of plans for the investigation and its risks and expected benefits, iii) public disclosure of sufficient information following completion of the research to apprise the community and researchers of the study, including the demographic characteristics of the research population, and its results, iv) establishment of an independent data monitoring committee to exercise oversight of the research, and 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 v) asking whether he or she objects to the subject's participation in the research.  The investigator will summarize efforts made to contact family members and make this information available to the IRB at the time of continuing review.”

C.  Additional Considerations for waiving informed consent in non-FDA regulated research :

In addition, the IRB is responsible for ensuring that the investigator has specific procedures in place for:

1.       informing, at the earliest feasible opportunity, each subject of the subject's inclusion in the research (or if the subject remains incapacitated, providing such information to the appropriate legally authorized representative of the subject), including the details of the research and other information contained in the Informed Consent Document. 

2.       informing the subject 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 (or if the subject remains incapacitated, providing such information to the appropriate legally authorized representative of the subject). 

3.       informing the subject of (1) and (2) as soon as feasible, in the case where the legally authorized representative was informed of (1) and (2) on behalf of the subject, and subsequently the subject’s condition has improved. 

4.       contacting a legally authorized representative of the subject (if feasible) with information about the research, if the subject was entered into research with waived consent and the subject died before the legally authorized representative could be contacted.

RESPONSIBILITY:

It is the responsibility of the principal investigator to contact the ORSP to plan for requirements for submission of research planned for emergency settings.  It is the responsibility of the OECO to consult with principal investigators to ensure public disclosure and comment and that all regulatory requirements are met.  It is the responsibility of the VCU IRB to ensure that the all responsibilities under 21 CFR 50.24 are fulfilled and to ensure that research is reviewed in accordance with 45 CFR 46.

REFERENCE:

FDA Language and Excerpts from Preamble

OHRP Informed Consent Requirements in Emergency Research

21 CFR 50.24

45 CFR 46.116(c)(2)

FDA Guidance: Exception from Informed Consent For Studies Conducted in Emergency Settings