Exception from Informed Consent: Viewpoint of Institutional Review Boards—Balancing Risks to Subjects, Community Consultation, and Future Directions

Differences in interpretation of the Final Rule for exception from informed consent (EFIC) requirements for emergency research result in inconsistencies in implementation and difficulties for some institutional review boards (IRBs) to approve such research. During a consensus workshop organized by the editorial board of Academic Emergency Medicine, participants discussed how IRBs balance the risks to human subjects in EFIC research, the conduct of community consultation and its role in IRB decision making, and future directions to improve and research EFIC effects. Areas of consensus and diversity of opinion were identified. During the workshop, the National Institutes of Health model of consensus building was used to develop statements pertaining to specific questions of the effects, directions, implementation, and ultimate goals for emergency research using EFIC. The program was composed of an overview of the history and issues related to EFIC or Final Rule research and presentations of viewpoints of experts in this area of research. A final consensus was developed regarding the major topics, including IRB perspective, effective community consultation (often considered the main difficulty in implementing EFIC research), and goals for future directions and research on the topic. Roundtable discussions and breakout sessions involving interested parties were used as a format. In regard to how IRBs balance risks, by consensus it was agreed the regulations stipulate that EFIC studies must involve treatment that is unproven or unsatisfactory. The committee agreed that resuscitation rates are currently unsatisfactory, and thus current treatments are unsatisfactory. Many treatments currently used as standard care have never been proven to be effective. IRBs and the public need education that resuscitation research is needed. The same can be said for other conditions to which this rule applies. Because IRB expertise differs across the country, a group of peer reviewers to act as consultants should be available to help IRBs determine if current treatment for a condition is unproven or unsatisfactory. In regard to community consultation, the experiences of others are important and helpful as guidance. The amount and formats of community consultation should correspond to the amount of risk involved in the study proposed. In regard to future directions, communities should be asked how they define “success” of community consultation and public disclosure. Research on community attitudes is critical. Ways to continue/add to research include the following: research including major National Institutes of Health/Centers for Disease Control and Prevention funding acquisition for evaluation of the clinical impact of EFIC research; education for research funding agencies about emergency research, including current outcomes (e.g., survival rates); participation of emergency medicine researchers in meetings of research ethicists/IRB members (Public Responsibility in Medicine and Research/Applied Research Ethics National Association); publication of experiences and of the effects of EFIC research; future update meetings such as this one at the Society for Academic Emergency Medicine meeting; and more membership on IRBs of emergency physicians. While IRBs must approve EFIC research based on their own local environment, additional guidelines from regulatory agencies may be helpful. In general, current treatments for EFIC conditions are unsatisfactory and many are unproven. A group of peer reviewers can act as consultants to IRBs that do not have this expertise.     

Risk in Emergency Research Using a Waiver of/Exception from Consent: Implications of a Structured Approach for Institutional Review Board Review

Objective: To apply component analysis, a structured approach to the ethical analysis of risks and potential benefits in research, to published emergency research using a waiver of/exception from informed consent. The hypothesis was that component analysis could be used with a high degree of interrater reliability, and that the vast majority of emergency research would comply with a minimal‐risk threshold. Methods: A Medline search and manual search were done to identify studies using a waiver of/exception from informed consent published between July 1996 and December 2000. A review panel of physicians and bioethicists independently classified nontherapeutic procedures in each study as minimal risk, probably minimal risk, or probably more than minimal risk. Results: Seventy studies using a waiver of/exception from informed consent were identified. A majority of reviewers classified nontherapeutic procedures in 62 studies (88.6%) as minimal risk. Reviewers classified nontherapeutic procedures in six studies (8.6%) as minimal risk or probably minimal risk. In two studies (2.9%), nontherapeutic procedures were classified as probably more than minimal risk. The intraclass correlation coefficient was 0.89 (95% CI = 0.85 to 0.93), indicating very high interrater reliability. Conclusions: Component analysis can be used with high reliability to review emergency research and may improve the consistency of institutional review board review of emergency research. The vast majority of published emergency research performed using a waiver of/exception from consent complies with a properly‐applied minimal‐risk threshold. A minimal‐risk threshold for nontherapeutic procedures protects subjects better than current U.S. regulations while permitting important emergency research to continue.     

Resuscitation Research Involving Vulnerable Populations: Are Additional Protections Needed for Emergency Exception from Informed Consent?

The application of basic ethical principles to resuscitation research and other research in the emergency and critical care settings presents a particular challenge. The emergency exception from informed consent (EFIC) rule (21 CFR 50.24 and 45 CFR 46.101[i]) addresses a particular vulnerability: that which occurs when persons cannot consent due to acute loss of decisional capacity. The question arises as to whether populations defined as “vulnerable” are unique within studies to which EFIC applies. This report details the proceedings of a breakout session of the 2005 Academic Emergency Medicine Consensus Conference, “Ethical Conduct of Resuscitation Research,” that dealt with this issue. Topics addressed were 1) the applicability of the term “vulnerable” in research using EFIC; 2) the relationship between vulnerability, exploitability, and capacity; 3) the significance of vulnerability in research design; 4) the adaptation of the informed consent process to the emergency setting; and 5) the role of the institutional review board. Ten consensus recommendations emerged from the discussion. Of particular importance was the endorsement of the idea that research using EFIC is as important in vulnerable populations as in the general population and that the systematic exclusion of vulnerable populations from resuscitation research is inappropriate.     

Informed Consent and Ethical Issues in Military Medical Research

Informed consent in military research shares many of the same fundamental principles and regulations that govern civilian biomedical research. In fact, much of modern research ethics is grounded in events that occurred in the context of war or government‐sponsored research. Despite these similarities and common origins, research in the military has additional requirements designed to preserve service members' informed consent rights. The special nature of the superior–subordinate relationship in the military necessitates careful protections to avoid perceptions of coercion or undue influence on a military subject. Additionally, current legal and regulatory requirements for advanced informed consent significantly restrict the flexibility of the military to conduct research using waiver of consent. This has implications on the ability of the nation to develop effective medical treatments for the global war on terrorism. Nevertheless, work is under way to realign defense research policy with the norms of civilian biomedical practice. Future directions include the adoption of waivers for military emergency research, and the cautious introduction of human subject studies on the battlefield. This paper discusses historical background, regulatory differences, and concerns and challenges of some of these regulatory differences for research personnel that apply to informed consent and waiver of said informed consent for emergency research conducted by the U.S. military.     

A study of warning letters issued to institutional review boards by the United States Food and Drug Administration

PURPOSE: This study explores the ethical issues contained in warning letters (WLs) issued to institutional review boards (IRBs) by the United States Food and Drug Administration (FDA). METHODS: The online FDA Warning Letter Index was reviewed for letters issued to IRBs in the United States under the violation categories "Institutional Review Board" and "IRB" for the period January 1997 through July 2004. The resultant letters were evaluated for violations in 4 regulatory themes: having and following written procedures for research review; documentation of research review; IRB membership and conflict of interest; and informed consent. RESULTS: Fifty-two (52) FDA WLs were issued to IRBs during this period. Hospital/medical centre IRBs received the most letters (n = 34), followed by university IRBs (n = 9) and private IRBs (n = 9). The most common regulatory violations were failure to have and follow adequate written procedures about how the review of research is conducted (50 WLs); failure to prepare and maintain adequate documentation of IRB activities (47 WLs); and failure to provide adequate continuing review of approved studies (36 WLs). Nineteen WLs were issued for consent form issues. CONCLUSIONS: Warning letters are informative with regard to clinical research regulations and research subject protection. The content of these letters consistently indicates weaknesses in review and documentation activities of audited IRBs, potentially signalling similar issues among IRBs across the United States. Our findings, in a setting of overburdened IRBs who, in general, passively monitor studies, raise concerns about study oversight and optimal protection of research subjects.     

EMS Providers and Exception from Informed Consent Research: Benefits, Ethics, and Community Consultation

Abstract Background. As attention to, and motivation for, emergency medical services (EMS)-related research continues to grow, particularly exception from informed consent (EFIC) research, it is important to understand the thoughts, beliefs, and experiences of EMS providers who are actively engaged in the research. Objective. We explored the attitudes, beliefs, and experiences of EMS providers regarding their involvement in prehospital emergency research, particularly EFIC research. Methods. Using a qualitative design, 24 participants were interviewed including nationally registered paramedics and Virginia-certified emergency medical technicians employed at Richmond Ambulance Authority, the participating EMS agency. At the time of our interviews, the EMS agency was involved in an EFIC trial. Transcribed interview data were coded and analyzed for themes. Findings were presented back to the EMS agency for validation. Results. Overall, there appeared to be support for prehospital emergency research. Participants viewed research as necessary for the advancement of the field of EMS. Improvement in patient care was identified as one of the most important benefits. A number of ethical considerations were identified: individual risk versus public good and consent. The EMS providers in our study were open to working with EMS researchers throughout the community consultation and public disclosure process. Conclusion. The EMS providers in our study valued research and were willing to participate in studies. Support for research was balanced with concerns and challenges regarding the role of providers in the research process.     

Researchers' Understanding of the Federal Guidelines for Waiver of and Exception from Informed Consent

The survival of patients who present to the emergency department with severe injury or illness is dismal. Resuscitation researchers are interested in advancing the science of resuscitation, and clinical studies must be conducted to determine the best treatment protocols. These studies must reflect good science and must balance individual patient autonomy and safety with scientific progress that benefits society as a whole. Researchers find the present federal guidelines on waiver of and exception from informed consent to be time consuming and expensive. They see variability in the requirements as interpreted by institutional review boards. There is confusion regarding the requirements for public notification and response to community consultation. They believe that the majority of the public, as well as health care professionals, want resuscitation research to progress, but a minority of people and governmental regulators are uncomfortable with waiver of and exception from informed consent for research studies. There is concern and some evidence that the federal guidelines have impeded the advancement of resuscitation science. Several strategies have been suggested to improve the situation. These include 1) better education of resuscitation researchers regarding the federal guidelines, 2) a toolbox for resuscitation researchers clarifying the guidelines, 3) advocacy for the advancement of resuscitation science as a public good, and 4) a national research advisory board that provides unbiased reviews of clinical studies and guidelines for local institutional review boards regarding risks, benefits, and communication strategies for waiver of and exception from consent proposals.     

Implementing the Food and Drug Administration's Final Rule for Waiver of Informed Consent in Certain Emergency Research Circumstances

In 1996, the Food and Drug Administration released its Final Rule for Waiver of Informed Consent in Certain Emergency Research Circumstances (the Final Rule). The Department of Health and Human Services (DHHS) also released an update of its regulations related to waiver of informed consent in emergency research. These new regulations allow resuscitation research to proceed with a waiver of informed consent under very narrow and specific clinical research circumstances. Waiving informed consent for research participation has profound ethical and scientific implications. However, in unpredictable life-threatening clinical situations for which current therapy is unproven or unsatisfactory, patients usually are unable to consent on their own behalf to participate in clinical trials of potentially beneficial but experimental interventions. Because of the time-dependent nature of most resuscitation interventions, it is usually not feasible to identify and contact the legally authorized representative who can speak on behalf of the patient within the presumed therapeutic window of the intervention under investigation. For such clinical trials to proceed, a waiver of informed consent is usually necessary. Patients who are critically ill or injured and unable to provide meaningful prospective informed consent because of their current life-threatening condition are vulnerable and require additional protections beyond those for research subjects who can speak on their own behalf. The Final Rule and the DHHS-updated regulations incorporate a number of additional patient safeguards that must occur if a clinical trial is to proceed with waiver of informed consent. Specific means of adequately meeting these requirements are not described in the regulations. Although this was intentional on the part of the federal regulators so that individual protocols and research environments would direct the development of these patient safeguards, the lack of specific guidance has led to confusion on the appropriate implementation of the new regulations. This article reviews some of the key concepts of the Final Rule, with suggestions on their purpose and meaning. It also reviews the studies that have been approved to date to proceed with waiver of informed consent, and offers suggestions for the process of implementing the requirements of the Final Rule for research involving patients who are unable to give prospective informed consent.     

Informed Consent for Medical Research: Common Discrepancies and Readability

Objective: To identify common discrepancies and average reading grade levels for informed consent forms (ICFs) us submitted to institutional review boards (IRBs) by medical researchers.
Methods: A retrospective evaluation of ICFs as submitted to IRBs of 3 university-affiliated hospitals during a I-year period. ICF content was evaluated using a checklist of 23 requirements specified in the federal regulations governing human research. Documents then were computer-analyzed to determine the readability scores using 2 common indexes of comprehension. A discrepancy was defined as any instance in which an ICF did not address an applicable requirement in the Code of Federal Regulations.
Results: Eighty-two ICFs representing 16 medical specialties were evaluated; 8 (10%) were from emergency medicine. Eighteen ICFs (22%) were conspicuously incomplete, lacking 29 federal requirements. The mean number of discrepancies was 4.7 (95% CI, 3.9–5.5) Common omissions included: a statement about who is doing the research, number of subjects in the study, circumstances when a subject's participation may be terminated, disclosure of alternative procedures, and notice to subjects regarding new findings. The mean Flesch grade level required to read all ICFs was 13.8 (95% CI, 13.5–14.2), implying that the majority of the U.S. adult population would be unable to comprehend these forms.
Conclusion: Designing a consent form to meet all of the federal requirements while maintaining a level of reading comprehension suitable for the general population is a difficult task for investigators.     

Does the Emergency Exception from Informed Consent Process Protect Research Subjects?

Although subject protection is the cornerstone of medical ethics, when considered in the context of research using emergency exception from informed consent, its success is debatable. The participants of a breakout session at the 2005 Academic Emergency Medicine Consensus Conference discussed the issues surrounding subject protection and advanced the following recommendations. 1) There are no outcome measures that define “protection”; therefore, it is not currently known whether or not subjects are protected under the current rules. 2) Care must be taken to protect not only the individual from harm during research but also to protect society from unregulated research in other countries and an inability to appropriately advance medical knowledge. 3) Some surrogate markers/methods of protection whose efficacies are debatable include data safety monitoring board activity, the community consultation and public notification (CC/PN) process, and institutional review board approval. 4) Minimal‐risk studies should be held to different standards of protection than those that involve more significant risk to the subject. 5) A handful of studies have been published regarding community consultation and notification, and the majority are case studies. Those that are specifically designed to discover the most successful methods are hindered by a lack of formal outcomes measures and tend to have negative results. 6) Follow‐up data from the CC/PN process should be disclosed to the Food and Drug Administration and incorporated into study designs. 7) Focus groups and/or random‐digit dialing have been suggested as promising methods for fulfilling the CC/PN requirements. 8) Studies need to be funded and performed that formally investigate the best means of CC/PN. 9) More funding for this research should be a priority in the emergency medicine and critical care communities. More data regarding terminated studies should be made available to the research community. 10) Quantifiable markers of success for CC/PN must be validated so that research may determine the most successful methods. 11) Data regarding subjects' and family members' experiences with exception from informed consent studies need to be obtained.     

Variation in Institutional Review Board Responses to a Standard Protocol for a Multicenter Clinical Trial

Multicenter clinical trials require approval by multiple local institutional review boards (IRBs). The Multicenter Airway Research Collaboration mailed a clinical trial protocol to its U.S. investigators and 44 IRBs ultimately reviewed it. OBJECTIVE: To describe IRB responses to one standard protocol and thereby gain insight into the advantages and disadvantages of local IRB review. METHODS: Two surveys were mailed to participants, with telephone follow-up of nonrespondents. Survey 1 was mailed to 82 investigators across North AMERICA: Survey 2 was mailed to investigators from 44 medical centers in 17 U.S. states. Survey 1 asked about each investigator's local IRB (e.g., frequency of meetings, membership), whereas survey 2 asked about IRB queries and concerns related to the submitted clinical trial. RESULTS: Both surveys had 100% response rate. Investigators submitted applications a median of 58 days (interquartile range [IQR], 40--83) after receipt of the protocol, and IRB approval took an additional 38 days (IQR, 26--62). Although eight applications were approved with little or no changes, IRBs requested an average of 3.5 changes per site. Changes involved study logistics and supervision for 45%, the research process for 43%, and the consent form for 91%. Despite these numerous requests, all eventually approved the basic protocol, including inclusion criteria, intervention, and data collection. CONCLUSIONS: The IRBs showed extreme variability in their initial responses to a standard protocol, but ultimately all gave approval. Almost all IRBs changed the consent form. A national, multicenter IRB process might streamline ethical review and warrants further consideration.     

An Approach to Community Consultation Prior to Initiating an Emergency Research Study Incorporating a Waiver of Informed Consent

OBJECTIVES: In November 1996, the Food and Drug Administration (FDA) and the Department of Health and Human Services (DHHS) enacted rules allowing a narrow exception to the requirement for prospective informed consent when enrolling critically ill patients in clinical research studies of emergency treatments. These rules require that, prior to initiation of the study, the applicable institutional review board (IRB) assess the acceptability of the proposed research study to members of the community in which the research will be conducted. Specifically, the IRB must perform community consultation-a process during which community members learn about the proposed research and communicate their opinions regarding its acceptability to investigators or IRB representatives. The FDA and DHHS rules do not define specific acceptable methods for performing this community consultation. The objective of this study is to demonstrate the feasibility and utility of one proposed method for performing such community consultation. METHODS: Parents of children being seen for minor traumatic injuries in three pediatric EDs were asked to participate in a study regarding informed consent. After consent, an instructor described to the parent a prospective, randomized, placebo-controlled trial of phenytoin for the prophylaxis of posttraumatic seizures in children with severe closed head trauma. All parents were then asked whether they would have consented for their own child's participation, if their child had suffered such head injury. The parents were further asked to explain the reason(s) for their responses. RESULTS: Parents of 227 children (children's mean +/- SD age 8.0 +/- 4.8 years, 57% male) were interviewed. Sixty-six percent of parents (149/227) stated they would give consent for their child's participation. Of the 149 consenting parents, 85% (126/149) cited potential benefit to their child, 72% (107/149) cited potential benefit to other children, and 60% (90/149) cited furthering medical knowledge. Of the 78 nonconsenting parents (34% of total), 54% (42/78) cited fear of adverse effects, 39% (30/78) did not want their child to be a research subject in general, 27% (21/78) believed they needed to discuss participation with family members who were unavailable, and 26% (20/78) stated they were unable to decide unless they were in the actual situation. Parental ethnicity and household income were found to influence the consent decision, while the parent's gender, religion, language, and educational level were not associated with the consent decision. CONCLUSIONS: Community consultation regarding the acceptability of an emergency research protocol can be obtained via interview techniques in the ED. This methodology may allow investigators to obtain data on opinion from a targeted community for IRB consideration during the review of emergency research studies proposing a waiver of informed consent.     

Exception from Informed Consent Enrollment in Emergency Medical Research: Attitudes and Awareness

Objectives
To explore attitudes surrounding exception from informed consent enrollment into research studies. In addition, the authors sought to determine the level of awareness of such an ongoing study among potential subjects, as defined by their presence in an emergency department (ED).
Methods
A convenience sample of urban academic ED patients and visitors was surveyed during a visit regarding their attitudes and awareness of an emergency exception from informed consent, blood-substitute trial ongoing in the community.
Results
There was a 13% refusal rate, and 32% of those approached had characteristics that met exclusion criteria. There were 497 surveys analyzed. There was a predominance of women, Caucasians, and persons with at least some college education. Only 39 (8%) of respondents reported awareness of the ongoing blood substitute trial, and only 19 (4%) were able to list a risk or benefit of participation. Education, income, and age were not associated with reported awareness. Male gender, younger age, awareness of the existing exception from informed consent study, and being married were associated with greater acceptability for such enrollment practices.
Conclusions
The overall awareness of an ongoing exception from informed consent trial after community consultation and notification was low. A population with potential for enrollment in such a study did not demonstrate a high degree of acceptance of such practices. There were differences among certain demographic groups in the degree of acceptance. These differences may guide institutional review boards and investigators in community-consultation strategies for future waiver of or exception from informed consent studies.     

Research Conditions That Qualify for Emergency Exception from Informed Consent

Medical research involving critically ill and injured subjects unable to provide informed consent can only be conducted under federal regulations that attempt to balance the need to develop lifesaving treatments with protection of research subjects' rights. Regulators, researchers, and medical ethicists have all struggled to define the conditions under which an emergency exception from informed consent is appropriate. Although research has been successfully conducted under the current regulations, confusion remains regarding the meaning of the regulations, the applicable conditions, and the best ways to balance the needs of future patients and the rights of research subjects. In May 2005, at the Academic Emergency Medicine Consensus Conference “Ethical Conduct of Resuscitation Research,” a breakout session was held on the research conditions that qualify for the emergency exception from informed consent process. Several recommendations emerged: 1) The definition of “life‐threatening condition” should be broadly interpreted to include serious disability as well as death. 2) Existing therapies should be considered “unsatisfactory,” even if partially effective, when serious risk of morbidity or mortality remains even with the best available treatment or when the adverse effects of the best available treatment are serious. 3) Research with the emergency exception should be performed only if sufficient evidence exists that the proposed intervention has a reasonable chance of benefit. 4) More evaluation is needed to determine the degree to which the current rules impede research. 5) Application of the current regulatory framework for abbreviated or waived consent in emergency research should be encouraged. 6) Further study should also address variability among institutional review boards, the goals of community involvement, and how best to engage and educate the public in research efforts using emergency exception from informed consent.     

Research Involving Participants With Impaired Consent Capacity: An Examination of Methods to Determine Capacity to Consent

ObjectiveTo examine methods of assessing consent capacity in research protocols involving participants with impaired consent capacity, and examine instruments used to evaluate research consent capacity.MethodsA retrospective review of 330 active research protocols involving participants lacking capacity to consent over a 10-year period (January 1, 2009, through March 1, 2019) was conducted to collect protocol characteristics (medical specialty, level of risk and type of study, consent and assent procedures, and type of vulnerable or protected population). Methods to assess consent capacity are described, and instruments to assess consent capacity are summarized.ResultsThe specialties most frequently involving participants with impaired consent capacity in research were Neurology (27.3%), Critical Care (16.7%), and Surgery (10%). Type of studies are observational (43.9%), clinical trials (33%), chart review (11.5%), biobank (6.1%), and biomarker (5.5%). Minimal risk (53.3%) outnumbered greater than minimal risk (46.7%) studies. Most obtained written informed consent (77%) and assent (40.9%). The most common method to assess consent capacity was direct assessment by investigators (32.7%). Only 86 (26%) studies used instruments to assess consent capacity. Of the 13 instruments used, the most common was the Evaluation of Decision-Making Capacity for Consent to Act as a Research Subject, and is the only instrument that assesses all four components of decisional capacity: understanding, appreciation, reasoning, and choice.ConclusionGenerally, there was lack of uniformity in determining capacity to consent to research participation. Very few studies used instruments to assess consent capacity. Institutional review boards can provide greater guidance for research consent capacity determination.     

Implementation of community consultation for waiver of informed consent in emergency research: one Institutional Review Board's experience.

BACKGROUND: This article describes how one Institutional Review Board (IRB) chose to implement the issue of waiver of consent for a research study involving brain trauma victims brought to an emergency department. METHODS: Presentations were conducted in the state of Mississippi among cultural and ethnic groups representative of Mississippi's demographic composition. Individuals from the neurotrauma research team, including neurosurgeons and nurse study coordinators, conducted all of the presentations. One IRB member served as an objective "community liaison" and attended all presentations. This individual administered evaluation forms to attendees that measured their levels of comprehension and acceptance for the use of waiver of consent in the brain trauma study. RESULTS: All of the 137 attendees in 7 community consultation meetings gave their approval for the use of "waiver of consent." Continued community consultations are planned for the duration of the brain trauma study. CONCLUSION: Based on our experience, we conclude that in collaborating with local IRBs, research teams can successfully develop strategies for obtaining "acceptable community consultations" as required by regulatory mandates. We suggest that standardized community consultation guidelines be developed for obtaining waivers of informed consent in emergency research. Such criteria should form the basis for local IRBs to obtain their respective community consultations.