Planned emergency research involves the systematic investigation of a condition experienced by individuals "in a setting where the emergency circumstances require prompt action and generally provide insufficient time and opportunity to locate and obtain consent from each subject's legally authorized representative" (FDA 2013).
In addition, "the research must have the prospect of direct benefit to the patient and must involve an investigational product that, to be effective, must be administered before informed consent from the subject or the subject's legally authorized representative can be obtained and in which there is no reasonable way to identify prospectively individuals likely to become eligible for participation. FDA Guidance
Planned emergency research is different than the emergency use of an investigational drug or device in a single patient. Emergency use of an investigational drug or device involves the treatment of a patient using an investigational drug or device outside of the research setting.
Per notice in the Federal Register (October 2, 1996) DHHS has waived the general requirements for informed consent for the class of research consisting of Emergency Research which falls under FDA regulations 21CFR50.24. Because informed consent cannot be obtained prior to initiating research procedures, there are many additional participant protections that must be in place before the IRB can approve planned emergency research.
Legally Authorized Representative (LAR): an individual, or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research. [45CFR.46.102(c) and 21CFR50.3(l)].
Family Member: Both FDA and DHHS define a "family member" as any one of the following legally competent persons: spouse; parents; children (including adopted children); brothers, sisters, and spouses of brothers and sisters; and any individual related by blood or affinity whose close association with the subject is the equivalent of a family relationship
Community Consultation: Providing the opportunity for discussion with, and soliciting opinions from, the community(ies) in which the study will take place and from which the study subjects will be drawn. These communities may not always be the same; when they are not the same, both communities should be consulted.
Public Disclosure (a) Before a planned emergency research protocol begins, the dissemination of information in the community(ies) in which the study will take place and from which the subjects will be drawn sufficient to allow a reasonable assumption that the communities are aware that the study will be conducted, and its risks and benefits; and (b) after the study has been conducted, the dissemination of information to the community(ies) in which the study was conducted and to scientific researchers sufficient to describe the study's demographic characteristics and the study's results
Therapeutic Window: The protocol defines the time period, based on available scientific evidence, during which the intervention under investigation in the planned emergency research might reasonably produce a demonstrable clinical effect.
Conditions Required to Conduct Planned Research in Emergency Settings with Wavier of Consent and WAIVER OF HIPAA AUTHORIZATION
The IRB reviews the protocol and subsequent informed consent procedures to ascertain "approvability." If the protocol is not approvable by the IRB-HSR, because it does not meet the requirements or there are ethical concerns, explanatory documentation must be promptly supplied to the investigator and sponsor.
The convened IRB determines whether the research activity is subject to 21 CFR 50. If the research is FDA regulated, the IRB follows the FDA regulatory criteria to allow an exception to the requirement to obtain consent (Sec. 50.24).
21 CRF 50.24 (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 of all subjects be obtained if the IRB (with the concurrence of a licensed physician* who is a member of the IRB and who is not otherwise participating in the clinical investigation) finds and documents each of the following points:
*Concurrence by an Independent Physician: The IRB must obtain the documented concurrence of a physician, licensed in the state where the research will occur, who is a member of or consultant to the IRB but who is not otherwise connected to the study or involved in the research, before approving an exception to informed consent for planned emergency research.
- Life Threatening Situation: 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. (all three must be true)
- Informed Consent is Not Feasible: The IRB must find that informed consent is not feasible because: (all three must be true):
- The subjects will not be able to give their informed consent as a result of their medical condition;
- The intervention under investigation must be administered before consent from the subjects' legally authorized representatives is feasible; and
- There is no reasonable way to prospectively identify the individuals likely to become eligible for participation in the clinical investigation.
- Prospect of direct benefit: The IRB must find that participation in the research holds out the proposal of direct benefit to the subject because: (all three must be true):
- Subjects are facing a life-threatening situation that necessitates intervention;
- 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
- 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.
- Research Impracticable in Absence of Waiver of Informed Consent: The IRB must find that the clinical investigation could not practicably be carried out without the waiver.
- Therapeutic Window: The IRB must find that the proposed investigational plan defines the length of the potential therapeutic window based on available scientific evidence.
- Informed Consent Process and Documents: The IRB must review and approve informed consent procedures and an informed consent document consistent with FDA and HHS regulations. The procedures for obtaining informed consent 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 must also review and approve 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 information below.
The consent process includes the following:
- The investigator has summarized efforts that will be made to contact and obtain consent from a legally authorized representative within the window of time rather than proceeding with consent (if feasible). The investigator will summarize efforts made to contact a legally authorized representative and make this information available to the IRB at the time of continuing review
- If obtaining 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 participant’s family member who is not a legally authorized representative, and asking whether he or she objects to the participant’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.
- If a legally authorized representative or family member is told about the clinical investigation and the participant’s condition improves, the participant is also to be informed as soon as feasible.
- If a participant is entered into a clinical investigation with waived consent and the participant dies before a legally authorized representative or family member can be contacted, information about the clinical investigation is to be provided to the participant’s legally authorized representative or family member, if feasible.
- Community Consultation and Public Disclosure: Researchers are required to complete community consultation and public disclosure activities. Full information about community consultation and public disclosure can be found in FDA Guidance, April 2013, including a list of the minimum requirements for each activity.
Researchers are required to describe the following in the IRB application/protocol:
- An appropriate plan for consultation with representatives of the communities in which the clinical investigation will be conducted and from which the participants will be drawn.
- An appropriate plan for public disclosure to the communities in which the clinical investigation will be conducted and from which the participants will be drawn, prior to initiation of the clinical investigation, of plans for the investigation and its risks and expected benefits.
- An appropriate plan for 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.
According to FDA 2013, community consultation means providing the opportunity for discussions with, and soliciting opinions from, the community in which the study will take place and the community from which the study subjects will be drawn. These communities may not always be the same; when they are not the same, both communities should be consulted.
The goals of community consultation are to:
- show respect for persons by informing the community about the study in advance;
- inform community members about the trial in advance and provide a means for affected communities to provide meaningful input to the IRB before its decision to approve, require modifications to, or disapprove the study;
- show respect for the community by allowing representatives of the community to identify potential community-level concerns and effects of the research; and
- show respect for subjects’ autonomy. Respect may be shown by including in community consultation activities individuals who may have, or be at risk for, the condition under study (and thereby obtain input from a group that is expected to be similar to the eventual study subjects).
According to FDA 2013, public disclosure means dissemination of information (i.e., one-way communication) to the community(ies), the public, and researchers about the emergency research.
The goal of public disclosure prior to initiation of the study is to provide sufficient information to allow a reasonable assumption that the broader community is aware of the plans for the investigation, its risks and expected benefits, and the fact that the study will be conducted without obtaining informed consent from most study subjects.
The goal of public disclosure after the study is completed is to ensure that the communities, the public, and scientific researchers are aware of the study’s results. Disclosure to researchers of the results, both positive and negative, of studies conducted under 21 CFR 50.24 is particularly important because such disclosure may help FDA and researchers learn from these studies involving vulnerable subjects who are unable to consent.
The IRB will determine whether it is appropriate for the IRB to carry out community consultation in addition to that performed by the investigator. Community consultation and public disclosure should engage the affected communities in discussion about the proposed research, with the possibility of appropriate modification to the design and/or conduct of the study as a possible outcome. The plan for consultation and disclosure should consider the following:
- Radio/TV advertisements
- Press releases - newspaper, press interviews
- Community meetings/gatherings
- Civic groups, churches, minorities organizations, public officials
- Target groups more likely to be involved
- Information related to procedures for opting out
- Independent Data Monitoring Committee: The PI’s plan to establish an independent data monitoring committee to exercise oversight of the clinical investigation;
- Separate IND/IDE: Evidence that the study will be performed under a separate investigational new drug application (IND) or investigational device exemption (IDE) that clearly identifies the research may include subjects who are unable to consent. (The requirement for a separate IND/IDE is required even if an IND for the same drug product or an IDE for the same device already exists). The initial IRB application for this research may not be submitted as an amendment under 21 CFR section 312.30 or 812.35.
- Verification that the protocol does not allow for the enrollment of prisoners or women known to be pregnant
- The IRB must find that the protocol has an appropriate plan for emergency testing prior to enrollment (if feasible and appropriate) or follow – up to ensure the safety of the pregnant woman or fetus after incidental enrollment. Any study procedures performed after pregnancy is identified must meet the criteria found in the
The IRB determinations are documented in the Scientific Reviewer Checklist: Planned Emergency Research and Exception from Informed Consent (EFIC)-as well as the IRB meeting minutes and retained by the IRB for at least 3 years after completion of the clinical investigation, and the records shall be accessible for inspection and copying by FDA in accordance with 21 CFR 56.115(b).
If an IRB determines that it cannot approve a clinical investigation because the investigation does not meet the criteria in the exception provided above 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 IRB's that have been, or are, asked to review this or a substantially equivalent investigation by that sponsor.
Vulnerable Populations: Children, Prisoners and Pregnant Women
Children: Children may be included in federally-funded emergency research under EFIC provided that the additional criteria for involving children in research are met. Most emergency research that meets the criteria for EFIC will also meet the criteria for inclusion of children because the research is greater than minimal risk but holds out the prospect of direct benefit to the subjects. If the study involves children, the community consultation and public disclosure plans should carefully consider how to reach parents of children who would potentially be included and, if appropriate, the children themselves. (See Vulnerable Populations Checklist-Children)
Prisoners: Per DHHS regulations, prisoners may not be included in federally-funded emergency research under EFIC. However, given the emergent circumstances under which subjects are enrolled in these studies, it may not be apparent that a subject is a prisoner at the time of enrollment. Likewise, a subject could become a prisoner following enrollment and during the study period (including long-term follow-up periods).
Therefore, the protocol should be clear that known prisoners will be enrolled and should address either: 1) the plan for safely removing subjects from the study who become prisoners after enrollment; or20 how the protocol meets the criteria for approval of research with prisoners with respect to the study procedures that take place after the emergency intervention .
Pregnant Women and Fetuses: Per DHHS regulations, pregnant women and fetuses may not be included in federally-funded emergency research under EFIC. However, given the emergent circumstances under which subjects are enrolled in these studies, it may not be apparent that a subject is pregnant. Investigators must carefully consider the impact that the study intervention could have on a pregnant women or fetus where the pregnancy is not identified at the time of enrollment. A plan for emergency testing prior to enrollment (if feasible and appropriate) or follow-up to ensure the safety of the pregnant woman or fetus after incidental enrollment should be described in the protocol. Any study procedures performed after pregnancy is identified must meet the criteria in Vulnerable Populations Checklist-Pregnant Women, Fetuses, Neonates)