Patient and Surrogate Postenrollment Perspectives on Research Using the Exception From Informed Consent: An Integrated Survey.

STUDY OBJECTIVE: It is important for researchers interested in trials using the exception from informed consent to understand the views and experiences of enrolled individuals. Previous studies have shown that patient and surrogate attitudes are generally positive. These studies were small and did not include pediatric patients, and interviews were often conducted long after trial enrollment. This study sought to explore attitudes toward exception from informed consent in a larger sample and more contemporaneous setting. METHODS: A 10-item paper-and-pencil survey was integrated into the Established Status Epilepticus Treatment Trial, a randomized trial of 3 treatments for benzodiazepine-refractory status epilepticus in pediatric and adult patients. Primary domains included attitudes toward trial enrollment, exception from informed consent, and community consultation. Simple descriptive statistics, χ2, and Fisher's exact tests were conducted. RESULTS: Of 317 patients and surrogates, 90% agreed with or were neutral about the statement "I am glad that I/my family member was included in the Established Status Epilepticus Treatment Trial research study," whereas 10% disagreed. Twenty-seven percent disagreed with enrollment in the study without prospective consent. Black participants were more likely than white, other race, and unknown-race participants to disagree with enrollment without prospective consent (36% versus 23%, 14%, and 14%, respectively). Participants indicated that patients (81%), their families (65%), and those at risk for seizures (51%) were most important to include in community consultation. CONCLUSION: This study aimed to explore attitudes toward exception from informed consent enrollment among participants at all sites in a large, multicenter exception from informed consent trial. General acceptance of trial enrollment was high; acceptance of exception from informed consent specifically was somewhat lower, especially among black participants. Our findings provide further support for targeted community consultation focusing on individuals with connections to the disease under study. Future research should focus on communication in the postenrollment period, especially with individuals who may have concerns about exception from informed consent.

A systematic review of Federal Drug Administration Docket for community consultation and public disclosure in exception from informed consent trials.

BACKGROUND: Exception from informed consent imposes community consultation and public disclosure requirements on clinical investigation in critically ill and injured patients. In 2011, the Food and Drug Administration instructed sponsors to submit publically disclosed information to the Food and Drug Administration Docket, but to date there has been no comprehensive analysis of available data. We summarized the community consultation and public disclosure practices of exception from informed consent trials published on the Food and Drug Administration Docket in order to better understand the breadth of common practices that exists among acute care clinical research. METHODS: We performed quantitative and qualitative analysis of Docket FDA-1995-S-0036 from its initiation until June 2017 in order to summarize existing practices. We developed a 4-point scoring system to categorize public disclosure and community consultation based on inclusion of key components such as a detailed plan, schedule of events conducted, results, and materials uploaded. RESULTS: The 177 docket submissions represented 34 trials. Material related to public disclosure accounted for 49% of pages, community consultation 45%, and 6% other. The median Docket Review Content Score for public disclosure was 3 (mean: 2.5, range: 0-4) and 2 (mean: 2.1, range: 0-4) for community consultation materials. CONCLUSION: The public information contained in the Docket varies broadly by trial and content. Additionally, as evidenced by the wide range of the Docket Review Content Score, submission guidelines are not followed uniformly. Given the apparent uncertainty about what should be submitted, and the need for best practice recommendations, it is valuable to categorize and summarize existing community consultation and public disclosure content.

Consulting communities when patients cannot consent: a multicenter study of community consultation for research in emergency settings.

OBJECTIVES: To assess the range of responses to community consultation efforts conducted within a large network and the impact of different consultation methods on acceptance of exception from informed consent research and understanding of the proposed study. DESIGN: A cognitively pretested survey instrument was administered to 2,612 community consultation participants at 12 U.S. centers participating in a multicenter trial of treatment for acute traumatic brain injury. SETTING: Survey nested within community consultation for a phase III randomized controlled trial of treatment for acute traumatic brain injury conducted within a multicenter trial network and using exception from informed consent. SUBJECTS: Adult participants in community consultation events. INTERVENTIONS: Community consultation efforts at participating sites. MEASUREMENTS AND MAIN RESULTS: Acceptance of exception from informed consent in general, attitude toward personal exception from informed consent enrollment, and understanding of the study content were assessed. Fifty-four percent of participants agreed exception from informed consent enrollment was acceptable in general in the proposed study; 71% were accepting of personal exception from informed consent enrollment. Participants in interactive versus noninteractive community consultation events were more accepting of exception from informed consent in general (63% vs 49%) and personal exception from informed consent inclusion (77% vs 67%). Interactive community consultation participants had high-level recall of study content significantly more often than noninteractive consultation participants (77% vs 67%). Participants of interactive consultation were more likely to recall possible study benefits (61% vs 45%) but less likely to recall potential risks (56% vs 69%). CONCLUSIONS: Interactive community consultation methods were associated with increased acceptance of exception from informed consent and greater overall recall of study information but lower recall of risks. There was also significant variability in exception from informed consent acceptance among different interactive consultation events. These findings have important implications for institutional review board and investigators conducting exception from informed consent research and for community engagement efforts in research more generally.

Community consultation for prehospital research: experiences of study coordinators and principal investigators.

OBJECTIVE: To assess principal investigators' and study coordinators' views and experiences regarding community consultation in a multicenter trial of prehospital treatment for status epilepticus conducted under an exception from informed consent for research in emergency settings. METHODS: Principal investigators and study coordinators at all 17 hubs for the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) were invited to complete a web-based survey regarding community consultation at their site for RAMPART. Major domains included 1) perceived goals of community consultation, 2) experiences with and views of community consultation methods used, 3) interactions with IRB regarding community consultation, and 4) general satisfaction and lessons learned. Descriptive statistics were tabulated for Likert scale data; relevant themes were reported for text-based data. RESULTS: Twenty-eight individuals (16 coordinators and 12 investigators) representing all 17 RAMPART hubs completed the survey. Respondents considered multiple community consultation goals to be important, with least support for the role of community consultation in altering study design. All sites used multiple methods (median = 5). The most widely used, and generally favored, method was attending previously scheduled meetings of existing groups. Respondents expressed frustration with low attendance and responsiveness at open public meetings. CONCLUSIONS: Coordinators and investigators in this trial viewed community consultation efforts as successful but reported real challenges generating public interest. Individuals with the condition under study were found to be more engaged and supportive of the trial. Respondents endorsed numerous potential goals of the community consultation process and often combined methods to achieve these goals.

Institutional Review Boards' Assessment of Local Context: A Mixed Methods Study.

The nature of the review of local context by institutional review boards (IRBs) is vague. Requirements for single IRB review of multicenter trials create a need to better understand interpretation and implementation of local-context review and how to best implement such reviews centrally. We sought a pragmatic understanding of IRB local-context review by exploring stakeholders' attitudes and perceptions. Semistructured interviews with 26 IRB members and staff members, institutional officials, and investigators were integrated with 80 surveys of similar stakeholders and analyzed with qualitative theme-based text analysis and descriptive statistical analysis. Stakeholders described what they considered to be local context, the value of local-context review, and key processes used to implement review of local context in general and for emergency research conducted with an exception from informed consent. Concerns and potential advantages of centralized review of local context were expressed. Variability in perspectives suggests that local-context review is not a discrete process, which presents opportunities for defining pathways for single IRB review.

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the United States. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 hours of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient reported quality of life measures. Discussion: In-vitro and in-vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration: ClinicalTrials.gov (NCT04217551, 2019-12-30).

Meeting unique requirements: Community consultation and public disclosure for research in emergency setting using exception from informed consent.

BACKGROUND: Exception from informed consent (EFIC) regulations for research in emergency settings contain unique requirements for community consultation and public disclosure. These requirements address ethical challenges intrinsic to this research context. Multiple approaches have evolved to accomplish these activities that may reflect and advance different aims. This scoping review was designed to identify areas of consensus and lingering uncertainty in the literature. METHODS: Scoping review methodology was used. Conceptual and empirical literature related to community consultation and public disclosure for EFIC research was included and identified through a structured search using Embase, HEIN Online, PubMed, and Web of Science. Data were extracted using a standardized tool with domains for major literature categories. RESULTS: Among 84 manuscripts, major domains included conceptual or policy issues, reports of community consultation processes and results, and reports of public disclosure processes and results. Areas of consensus related to community consultation included the need for a two-way exchange of information and use of multiple methods. Public acceptance of personal EFIC enrollment is commonly 64% to 85%. There is less consensus regarding how to assess attitudes, what "communities" to prioritize, and how to determine adequacy for individual projects. Core goals of public disclosure are less well developed; no metrics exist for assessing adequacy. CONCLUSIONS: Multiple methods are used to meet community consultation and public disclosure requirements. There remain no settled norms for assessing adequacy of public disclosure, and there is lingering debate about needed breadth and depth of community consultation.

Patient Engagement in Neurological Clinical Trials Design: A Conference Summary.

OBJECTIVES: The conference objectives included educating patients and advocates about clinical trials, educating the clinical research community about patient perspectives on participating in clinical trial design, and identifying strategies to increase participation in clinical trial design for neurological disorders. DESIGN: Observations were noted during a 1-day conference attended by patients, patient advocates, clinical trial staff, and investigators. The conference offered didactic sessions, small, and large group discussions. PARTICIPANTS: Conference participants were patients, patient advocates, clinical trial staff, students, and investigators interested in engaging patients in clinical trial design for neurological disorders. MEASURES: Conference participants were asked to consider lessons learned that could increase patient engagement in clinical trial design. RESULTS: We found that there is growing interest in including patients in the design of clinical trials for neurological disorders. Several themes emerged on how to move forward: networking; the multifaceted roles of advocates in research; training and education; creating patient-researcher partnerships; and clinical trials regulation issues. CONCLUSIONS: The conference provided a forum for dialogue regarding stakeholder engagement in the design of clinical trials for neurological disorders. This experience provides a template for replication and dissemination of this conference and informs next steps to accelerate the pathway from dialogue to action.

Balancing ethical goals in challenging individual participant scenarios occurring in a trial conducted with exception from informed consent.

In 1996, federal regulations were put into effect that allowed enrollment of critically ill or injured patients into Food and Drug Administration (FDA)-regulated clinical trials using an exception from informed consent (EFIC) under narrowly prescribed research circumstances. Despite the low likelihood that a legally authorized representative (LAR) would be present within the interventional time frame, the EFIC regulations require the availability of an informed consent process, to be applied if an LAR is present and able to provide prospective consent for patient enrollment into the trial. The purpose of this article is to describe a series of unanticipated consent-related questions arising when a potential surrogate decision-maker appeared to be available at the time of patient enrollment into a trial proceeding under EFIC.

Emergency research: using exception from informed consent, evaluation of community consultations.

BACKGROUND: In 1996, the U.S. Food and Drug Administration approved regulations authorizing an exception from informed consent (EFIC) for research conducted in emergency settings when obtaining prospective informed consent is not possible due to the potential subject's critical illness or injury. The regulations require that investigators conduct community consultation (CC) efforts before initiating a study and require that institutional review boards review the results of CC prior to approving a study. However, little is known about how communities view EFIC research or the CC process. OBJECTIVES: The objective was to assess the views of CC meeting attendees regarding the CC process, their understanding and views of EFIC research relating to the specific research trial under discussion, and their level of trust in physician-investigators. METHODS: Following CC meetings at two study sites (San Francisco and Atlanta) for the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), an active comparison, randomized trial of prehospital treatment for status epilepticus, the authors administered a pair of surveys to participants. One survey focused on CC experiences (CC survey) and trust in physician-investigators; the second assessed participants' understanding of EFIC and the RAMPART clinical trial design (EFIC survey). RESULTS: A total of 317 individuals participated in one of the two most popular types of CC meetings (group meetings and focus group sessions) at both sites. A total of 189 participants (59%) completed the CC survey and trust questions, and 297 (92%) completed the EFIC survey. Of those who completed the CC survey, 173 of 189 (92%) were very satisfied with the meeting, and 174 of 189 (92%) felt that they learned a lot about research at the meeting. A total of 169 of 189 participants (88%) felt that researchers heard the community's concerns, while only 106 of 189 (56%) said researchers would be willing to make changes to the study based on their concerns. Of those who completed the EFIC survey, 261 of 297 (88%) supported the study, 207 of 297 (70%) said they would agree to participate in the study, and 203 of 297 (68%) reported that they would agree to consent a loved one into the study. On a recently validated scale measuring trust in physician-investigators, participants at both sites seemed to have higher levels of trust in physician-investigators than the validation study population. CONCLUSIONS: Overall, members of these two communities expressed satisfaction with the CC session and had relatively high levels of support for the study and trust in physician-investigators.

Implementation of the exception from informed consent regulations in a large multicenter emergency clinical trials network: the RAMPART experience.

Clinical trials investigating therapies for acutely and critically ill and injured patients in the earliest phases of treatment often can only be performed under regulations allowing for exception from informed consent (EFIC) for emergency research. Implementation of these regulations in multicenter clinical trials involves special challenges and opportunities. The Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), the first EFIC trial conducted by the Neurological Emergencies Treatment Trials (NETT) network, combined centralized resources and coordination with retention of local control and flexibility to facilitate compliance with the EFIC regulations. Specific methods used by the NETT included common tools for community consultation and public disclosure, sharing of experiences and knowledge, and reporting of aggregate results. Tracking of community consultation and public disclosure activities and feedback facilitates empirical research on EFIC methods in the network and supports quality improvements for future NETT trials. The NETT model used in RAMPART demonstrates how EFIC may be effectively performed in established clinical trial networks.