Special Requirements and Guidance for Investigators
WPP #: XVII-16
Planned Emergency Research, Exception from Informed Consent, and Waiver of Applicability of Informed Consent
06-20-00; 11-12-01; 06-07-04; 06-21-06; 2-05-07; 6-15-2010
To assist investigators in planning, and the IRB in reviewing, protocols meeting the requirements for research that is designed for life-threatening emergency situations, including the requirements that must be met for exception from, or waiver of applicability of, informed consent in these situations.
- Emergency Setting Research
The term "Emergency Setting Research" refers to human subjects research designed to test medical interventions, drugs, or devices in urgent, life-threatening situations.
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 and/or ORCE is strongly recommended. Note that all research planned for emergency settings is reviewed by the VCU IRB regardless of funding source. Research that is planned for the emergency setting requires strict attention to regulations found in 21 CFR 50.24 for FDA regulated research, which describe the process for 'exception to informed consent.' There is also a separate provision for waiving the 45 CFR 46 requirement to obtain prospective informed consent for emergency research that is not FDA-regulated. The latter provision is seldom used at VCU.
FDA and OHRP provide guidance documents to inform the planning and implementation of planned emergency research. These are followed closely by the IRB, and the PI is expected to incorporate their guidance into protocol design. This WPP is an adjunct to the FDA and OHRP guidance and will be used in conjunction with their guidance and regulations. Enclosed text boxes indicate verbatim regulatory language.
Guidance for FDA-regulated research in the planned emergency setting:
- 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 exceptions from prospective informed consent for the conduct of FDA-regulated planned research in life-threatening emergent situations.
- Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency Research – DRAFT Guidance, July 2006 This guidance document, although in draft form, is the most current thinking of the FDA regarding planned emergency research. Use of this document is recommended.
Guidance for non-FDA-regulated research in the planned emergency setting:
- The 1996 OPRR (now, OHRP) Report titled ”Informed Consent Requirements in Emergency Research. “Description of 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. The ‘Emergency Research Consent Waiver’ may be used for research involving children, but is not applicable to Subpart B (pregnant women, fetuses, neonates) or to Subpart C (prisoners).
- IRB review of FDA-regulated Emergency Setting Research – Exception from Informed Consent (EFIC)
This WPP supplements the FDA Draft Guidance (indicated above) and federal regulations at 21 CFR 50.24 by offering additional considerations for the PI in designing, and the IRB in reviewing, the EFIC protocol. Particular areas of emphasis are: 1) preliminary approval of the protocol and subsequent informed consent procedures, 2) approval of a community consultation plan and its implementation, 3) approval of public disclosure before study initiation and at the completion of the study, 4) approval to begin enrollment in the research. The exception from informed consent requirements apply not only to investigational use of therapeutic products, but also to in vitro diagnostic device studies that meet all the requirements of 21 CFR 50.24. An organizational submission checklist for investigator and IRB purposes is added in an appendix.
- Preliminary approval of the protocol and subsequent informed consent procedures
The IRB reviews the protocol and subsequent informed consent procedures to ascertain ‘approvability.’ If the protocol is not approvable by the IRB, because it does not meet the requirements or there are ethical concerns, explanatory documentation must be promptly supplied to the investigator and sponsor.
For this step, the IRB must find and document the following, as per 21CFR50.24(a) (regulations are inserted verbatim into text boxes):
- 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.
- Obtaining informed consent is not feasible because: a) The subjects will not be able to give their informed consent as a result of their medical condition; b) the intervention under investigation must be administered before consent from the subjects’ LARs is feasible; and c) there is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the clinical investigation.
- 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.
- The clinical investigation could not practicably be carried out without the waiver.
- 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 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.
- The IRB with 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 finds and documents each of the following:
- Additional protections of the rights and welfare of the participants will be provided, including, at least:
- Procedures are in place to inform, at the earliest feasible opportunity, each participant, or if the participant remains incapacitated, a legally authorized representative of the participant, or if such a representative is not reasonably available, a family member, of the participant’s inclusion in the clinical investigation, the details of the investigation and other information contained in the consent document.
- There is a procedure to inform the participant, or if the participant remains incapacitated, a legally authorized representative of the participant, or if such a representative is not reasonably available, a family member, that he or she might discontinue the participant’s participation at any time without penalty or loss of benefits to which the participant is otherwise entitled.
- 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.
- The protocol is performed under a separate investigational new drug application (IND) or investigational device exemption (IDE) that clearly identified such protocols as protocols that might include participants 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.
- If an IRB determines that it cannot approve a clinical investigation because the investigation does not meet the criteria in the exception or because of other relevant ethical concerns, the IRB must document its findings and provide these findings promptly (no longer than within 30 days) in writing to the clinical investigator and to the sponsor of the clinical investigation.
Tips for preliminary review and approval by the IRB:
- See Section II in the FDA Draft Guidance document for further description of ‘prospect of direct benefit’, ‘practicability’, ‘subject exclusion,’ and ‘study design.’
- Also see Section II for further description of ‘therapeutic window rationale,’ ‘therapeutic window’ for in vitro diagnostic device studies, and contact of family members.
- The IRB evaluates the relative risk of the research based on standard of care locally and in other regions. Areas to include in a risk assessment include, but are not limited to, the following: medical risk, risk of standard of care in a research context, risk of using investigational drugs and devices in the setting, risks of offending the cultural sensibilities of the community, etc. See the references at the end of this WPP for more information.
- The PI is to provide information about the prevalence of the particular condition being studied according to an ‘exception from informed consent.’ Such information should include the frequency of presentation to the VCU Emergency Department (ED) as well as to the EDs of other institutions with which VCU is collaborating. If the research begins in the field, provide geographic references and frequencies for emergency intervention.
- The PI is invited to address the IRB at the first meeting at which the protocol will be reviewed. The PI or research staff should be available, if necessary, to answer questions at all subsequent IRB meetings where the protocol is reviewed.
- For EFIC studies originating in the field, the PI provides information about human subjects and protocol training for first responders. Collaborating first responder organizations are to have an FWA in place and provide their own IRB review, or request to defer to the VCU IRB.
- Issues of informed consent as noted above in regulation and in the Guidance Document are fully addressed. Note that the PI is to provide an informational script to be read to an available LAR in order to provide an opportunity for objection to participation prior to when the intervention is applied. The PI also provides a plan for notifying subjects who regain decisional capacity, and/or the LAR, about the subject’s participation in the research and request consent for continued participation. Informed consent forms/assent forms are submitted for review by the IRB. These should be first submitted in English, with subsequent submission translated by a duly qualified translator. See WPP XI-5 for more information.
- If children are included in the research, ensure that additional regulatory criteria is addressed, i.e. Subpart D, 21 CFR 50.50. Pregnant women and prisoners are excluded from this research.
- The inclusion of children and other scientific aspects of the study may require that the IRB consult with experts. Such consultation is carefully documented.
- The IRB should ask for PI clarification about whether the ambulance, after picking up the patient/subject, is directed to the nearest ED or bypasses in favor of an ED participating in the research. If the latter occurs, the IRB should consider how and whether emergency treatment is impacted and how research risk is affected.
- The ‘preliminary approval’ by the IRB means that the study will likely be approved when and if community consultation demonstrates a positive consensus in the community. Additionally, the public disclosure phase also requires a positive response by the community.
- With the ‘preliminary approval’ letter to the PI, the IRB should indicate that the community consultation plan should be submitted, if it has not already been.
Approval of a community consultation plan and its implementation (this step may be done in conjunction with Step 1 above)
The required community consultation aspect for EFIC research has ethical goals that include enhanced protections and benefits for the community participants, and legitimacy and shared responsibility for the conduct of the research by informing the impacted community and soliciting its views. The ‘community’ may have a geographic identity as well as a condition-specific identity that need not depend on living in the research catchment area.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
The submitted protocol must include a plan for community consultation. Community consultation activities are “designed to help ensure that the communities in which the emergency research will be conducted and from which subjects will be drawn are adequately informed about the risks and expected benefits of the research and are given the opportunity to ask questions about it as well as express their views prior to the IRB making a determination about the research.” (2006 Draft Guidance Document). Section VIII of the Draft Guidance Document provides extensive information about community consultation.
Tips for investigators and the IRB about community consultation:
- Identify community groups within the research catchment area whose geographic location, illness condition, or other characteristics increase their susceptibility or risk for being involved in the research. Identifying group ‘leaders’ who are willing to function as intermediaries for continued communication about the study is helpful. PI and/or IRB consultation with the VCU community research liaison is encouraged.
- The contribution of non-affiliated IRB members is very important in this endeavor. If possible, a non-affiliated member should serve as secondary reviewer on the protocol.
- The plan for community consultation requires full board approval. Outside meetings with the PI/research staff may be necessary to facilitate the process. A designated IRB representative should be the primary contact with the PI/staff about matters related to community consultation.
- All materials utilized in community consultation, including presentations and tools designed to elicit feedback, are to be IRB approved.
- Community consultation should make every effort to reach out to limited-English proficient individuals who may be susceptible to becoming research subjects in the study. All materials designated for community consultation activities should first be IRB approved in English. Translations by duly qualified translators are subsequently submitted for IRB approval. See WPP XI-5 for more information.
- Plan for at least 10 meetings with affected groups, depending on the risk of the research and the size of the community potentially impacted by the research. Meetings can be town hall style or can be added onto a regularly scheduled meeting of the group. The latter generally ensures a larger number of participants. The number of meetings and additional susceptible populations may be further identified by the IRB.
- Plan to advertise the meetings via mainstream and alternative media, if possible. Publicity that asks for feedback about the study is also solicited via websites, material distributed in faith communities or other settings frequented by identified susceptible groups. PI and/or IRB consultation with VCU Media Services is encouraged, especially to devise additional ways to solicit feedback from the community. A multi-faceted approach is recommended. Random digit dialing, as a method to survey large portions of the community, is another way to solicit opinion and feedback. However, it is not required.
- When the community consultation plan has been approved, the PI implements the plan. The PI and co-PIs are expected to present the study at these meetings in a way that is understandable to a lay audience. Transcripts and other feedback, such as anonymous survey results, are provided to the IRB for review. IRB members are encouraged to attend one or more community consultation meetings.
- The IRB must approve that community consultation has been ‘adequate.’ ‘Adequacy’ generally means that an acceptable number of individuals have been directly exposed to consultation activities and the preponderance of the feedback has been positive toward the research. Plan on ‘touching’ at least 100 individuals who could be potential subjects. This number is highly fluid and subject to IRB request.
- Approval of public disclosure before the study begins and after the completion of the study:
Public disclosure means dissemination of information about the emergency research sufficient to allow a reasonable assumption that the communities are aware of the plans for the investigation, its risks and expected benefits. At this phase, it is likely that the study will be conducted, however a largely negative response to public disclosure by the community may cause the IRB to reconsider.
Additional protections of the rights and welfare of subjects will be provided, including, at least:
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;(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;
See Section VIII-B in the Draft Guidance document for specific information about methods suggested by the FDA for public disclosure.
Additional tips for investigators and the IRB on Public Disclosure:
- Plan to send public disclosure materials to many, if not most, of the same venues receiving community consultation materials. Utilize identified group ‘leaders’ if possible.
- A lengthy description of risks and expected benefits may not be feasible in all of the disclosure materials. Ensure that a website and telephone number are included on all public disclosure materials.
- The IRB approves the public disclosure plan to occur before the study begins, prior to the plan’s publication and dissemination
- The PI provides a summary of the information that was disclosed, which is approved by the IRB as having been adequate. In some cases, pieces of the disclosure plan may not have been implemented due to unforeseen circumstances. The summary explains these exceptions.
- Submit a plan for public disclosure to take place after completion of the study. This plan may include many of the same features as the plan for disclosure prior to the initiation of the study and must be approved by the IRB. Any meetings can be town hall style or can be added onto a regularly scheduled meeting of the group, perhaps revisiting some of the same groups or venues. Since study completion may not occur for years, the plan may need re-review by the IRB before its implementation at the completion of the study.
- At the IRB’s discretion, the PI may be asked to provide plans for continued public disclosure at intervals during the course of the research, especially if the research will continue for a year or more. Such plans may be required and approved at the IRB’s request. The PI is expected to provide a public disclosure summary of each implementation during the course of the research.
IRB approval of the research to begin enrollment
The IRB must also find and document the following, as per 21CFR50.24(a):
Additional protections of the rights and welfare of subjects will be provided, including, at least:
(iv) Establishment of an independent data monitoring committee to exercise oversight of the clinical investigation; and (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 especially Sections II, III, IV, V, IX, and X in the EFIC Draft Guidance for full information on these regulatory requirements..
Tips for the IRB in approving the research to begin enrollment:
- Verify that an IND or IDE, as appropriate, exists for the agents used in an investigational manner in the study protocol
- Ensure that an independent data monitoring committee has been established
- See Section IX in the Draft Guidance document for further description of the PIs commitment to inform the legally authorized representative about the study prior to administration of the test article and after such administration.
- Ensure that all regulatory aspects are considered before final approval. For example, the EFIC criteria at 50.24 must be fully addressed, in addition to regulatory criteria for children.
- Ensure that a licensed physician concurs with the initiation of the study and with continuing review. The licensed physician member’s affirmative vote or licensed physician consultant’s concurrence should be recorded in the minutes.
- The IRB should consider the frequency of continuing review.
- The IRB promptly provides to the sponsor, in writing, a copy of the information that has been publicly disclosed about the initiation of the study under 50.24a7ii and 21CFR56.109g
- Any site additions or modifications to the protocol must be approved by the IRB prior to implementation, including site-specific community consultation and public disclosure.
- Protocol violations have the potential to lessen public support for the research if they are numerous or become widely known. Accordingly the approval letter should contain a statement encouraging the PI to act very promptly with a corrective action plan whenever violations of enrollment or treatment occur.
- Preliminary approval of the protocol and subsequent informed consent procedures
- IRB review of research not subject to FDA regulations according to the waiver of applicability of the requirement in 45CFR46 to obtain and document informed consent
As noted above, this provision in emergency setting research is seldom used at VCU. Nonetheless, the PI and IRB should know that it is available. Although there are many similarities with EFIC requirements for FDA-regulated research, the OHRP guidance document should be consulted for further information (The 1996 OPRR (now, OHRP) Report titled ”Informed Consent Requirements in Emergency Research.)
It is the responsibility of the principal investigator to contact the ORSP to plan for requirements for submission of research planned for emergency settings utilizing exception from informed consent or waiver of applicability of informed consent. It is the responsibility of the ORCE to consult with principal investigator and IRB to ensure adequate community consultation and public disclosure 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, as well as other FDA regulatory criteria for protocol review, and to ensure that research is reviewed in accordance with 45 CFR 46.
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
Halperin, H., Paradis, N., Mosesso, V. et al (2007) Recommendations for Implementation of Community Consultation and Public Disclosure under the Food and Drug Administration’s “Exception form Informed Consent Requirements for Emergency Research.” Circulation, 116, 1855-63.
Mitka, M. (2007). Aiding Emergency Research Aim of Report on Exceptions to Informed Consent. JAMA, 298(22), 2608-9.
VCU IRB SUBMISSION Checklist
Required for Research Involving
Planned Emergency Research, Exception FROM INFORMED CONSENT, AND WAIVER OF APPLICABILILTY OF INFORMED CONSENT
The purpose of this VCU IRB submission checklist is to assist the principal investigator in including the documents for review by the IRB, and help understand the IRB process. The following documents will ultimately be included in your submission. See the steps below for specific submissions.
The following documents will be reviewed and considered for approval in the preliminary stage:
Note: The following documents should be submitted at the time of initial submission.
- VCU IRB Submission form
- VCU IRB Research Plan
- Sponsor’s Protocol
- Research Funding Proposal
- FDA form 1572
- IND or IDE application
- Investigator’s Brochure
- Conflict of Interest Reporting Forms
- Principal Investigator CV & Medically Responsible Investigator CV (if applicable)
- Written request for the VCU IRB to serve as the IRB of record, as applicable
The following documents will be reviewed and considered for approval in the community consultation stage:
Note: The following documents should be submitted at the time of initial submission. Based on the type of study the IRB may request additional documents to be submitted.
- Community Consultation Plan – who are community representatives of potential subjects and why are these groups representative?
- Community Consultation Presentation(s) – may be multiple and tailored to different groups
- Community Consultation Evaluation form
- Community Consultation Questionnaire
- Sign in Sheet for Community Consultation Conference
- Power Point Presentation – is this understandable for the various target groups?
- Advertisements and information about planned community consultation
- Opt-Out form
- Website Advertisement
- List of Community Venues
- LAR Notification Letter
The following documents will be reviewed and considered for approval in the pre-study start public disclosure stage:
Note: The following documents should be submitted after the completion of the community consultation. Based on the type of study the IRB may request additional documents to be submitted.
- PIs summary and assessment of community consultation and the acceptability/ appropriateness of the study for the community, within groups and at large
- Public Disclosure Plan
- Dictations/Minutes from the Community Consultation meetings
- Advertisements and information about planned community consultation
- Publication Advertisements (during study)
- Informed Consent/Assent Documents
- Special Population form (if applicable)
The following document will be reviewed and considered for approval to begin enrollment:
Note: The following document should be submitted before the study begins enrollment.
- Public Disclosure Summary Report
Provide on-going public disclosure plans (and how these will be funded) if the study is planned to enroll for more than 6 months.