Informed Consent Trials Research Articles

Analysis of time to regulatory approval in an exception from informed consent trial in trauma patients

BACKGROUND The interactive media–based approach to community consultation and public disclosure (CC/PD), a key step when conducting exception from informed consent (EFIC) clinical trials, is intended to be completed in 4 months. This analysis characterizes the process, from initiation of CC/PD activities to institutional review board approval, to better understand the barriers and how these can be mitigated. METHODS This is a retrospective post hoc analysis of data collected as part of the CC/PD campaigns conducted for a large trial involving up to 90 trauma centers in the United States. Each site was provided with templated materials that had been reviewed and approved by a central institutional review board (cIRB). We collected the dates of milestones, including the study “kickoff call,” start of the social media campaign, dates of online community meetings, date of submission of site report to the cIRB, and cIRB approval date. RESULTS Sixty-two sites were cIRB approved at the time of this analysis. The median time from the kickoff call to the start of the social media campaign was 79 days, with an interquartile range of 33 to 126 days (range, 0–285 days). All social media campaigns ran for the prescribed period of at least 2 months. All sites conducted at least four online community meetings. The median number of days from the kickoff call to cIRB approval was 216 days (interquartile range, 168–281 days; range, 116–459 days). There was no significant difference between sites that had previous experience of EFIC trials. CONCLUSION Using the interactive media–based approach, CC/PD can be completed quickly; however, there are barriers that can incur substantial delays. Greater harmonization of local administrative processes would shorten the time to conduct CC/PD activities and facilitate the timely commencement and execution of EFIC trials. LEVEL OF EVIDENCE Systematic Review without Meta-analysis; Level III.

Willingness to participate in an active exception from informed consent trial in the pediatric intensive care unit.

Willingness to participate in an active exception from informed consent trial in the pediatric intensive care unit.

Design and implementation of community consultation for research conducted under exception from informed consent regulations for the PreVent and the PreVent 2 trials: Changes over time and during the COVID-19 pandemic.

Emergency clinical research has played an important role in improving outcomes for acutely ill patients. This is due in part to regulatory measures that allow Exception From Informed Consent (EFIC) trials. The Food and Drug Administration (FDA) requires sponsor-investigators to engage in community consultation and public disclosure activities prior to initiating an Exception From Informed Consent trial. Various approaches to community consultation and public disclosure have been described and adapted to local contexts and Institutional Review Board (IRB) interpretations. The COVID-19 pandemic has precluded the ability to engage local communities through direct, in-person public venues, requiring research teams to find alternative ways to inform communities about emergency research. The PreVent and PreVent 2 studies were two Exception From Informed Consent trials of emergency endotracheal intubation, conducted in one geographic location for the PreVent Study and in two geographic locations for the PreVent 2 Study. During the period of the two studies, there was a substantial shift in the methodological approach spanning across the periods before and after the pandemic from telephone, to in-person, to virtual settings. During the 10 years of implementation of Exception From Informed Consent activities for the two PreVent trials, there was overall favorable public support for the concept of Exception From Informed Consent trials and for the importance of emergency clinical research. Community concerns were few and also did not differ much by method of contact. Attendance was higher with the implementation of virtual technology to reach members of the community, and overall feedback was more positive compared with telephone contacts or in-person events. However, the proportion of survey responses received after completion of the remote, live event was substantially lower, with a greater proportion of respondents having higher education levels. This suggests less active engagement after completion of the synchronous activity and potentially higher selection bias among respondents. Importantly, we found that engagement with local community leaders was a key component to develop appropriate plans to connect with the public. The PreVent experience illustrated operational advantages and disadvantages to community consultation conducted primarily by telephone, in-person events, or online activities. Approaches to enhance community acceptance included partnering with community leaders to optimize the communication strategies and trust building with the involvement of Institutional Review Board representatives during community meetings. Researchers might need to pivot from in-person planning to virtual techniques while maintaining the ability to engage with the public with two-way communication approaches. Due to less active engagement, and potential for selection bias in the responders, further research is needed to address the costs and benefits of virtual community consultation and public disclosure activities compared to in-person events.

Community consultation in the pediatric intensive care unit for an exception from informed consent Trial: A survey of patient caregivers

AimTo explore perspectives of families in the pediatric intensive care unit (PICU) about an emergency interventional trial on peri-arrest bolus epinephrine for acute hypotension using Exception From Informed Consent (EFIC). MethodsWe performed face-to-face interviews with families whose children were hospitalized in the PICU. A research team member provided an educational presentation about the planned trial and administered a survey with open- and closed-ended items. Analyses included descriptive statistics for quantitative data and thematic analysis for qualitative data. ResultsSixty-seven participants contributed to 60 survey responses (53 individuals and 7 families for whom 2 family members participated). Most participants answered favorably toward the planned trial: 55/58 (95%) reported that the trial seemed “somewhat” or “very important”; 52/57 (91%) felt the use of EFIC was “somewhat” or “completely acceptable”; and 43/58 (74%) said they would be “somewhat” or “very likely” to allow their child to participate. Five themes emerged supporting participation in the planned trial: 1) trust in the clinical team; 2) familiarity with the study intervention (epinephrine); 3) study protocol being similar to standard care; 4) informed consent during an emergency was not feasible; and 5) importance of research. Barriers to potential participation included requests for additional time to decide about participating and misconceptions about study elements, especially eligibility. ConclusionsFamilies of PICU patients generally supported plans for an emergency interventional trial using EFIC. Future inpatient EFIC studies may benefit from highlighting the themes identified here in their educational materials.

Interactive media-based community consultation for exception from informed consent trials: How representative should (and can) it be?

Community consultation (CC) is a requirement for exception from informed consent (EFIC) research. This article explores the issue of how representative such consultations can and should be, with particular reference to the use of media-based activities. Interactive, media-based CC strategies are gaining traction, because they have much greater reach than traditional methods, but the increasing use of such methods has also led to calls to ensure that those contacted are representative of the community at risk. However, this is more complex than at first apparent. This article examines the question of how the "trauma community" should be defined, and what characteristics might be used to assess whether a sample of this community is representative. It also considers what data are actually available in order to satisfy such requirements.

An Approach to Reviewing Local Context for Exception from Informed Consent Trials Using a Single IRB.

In the context of emergency research, researchers can ask the institutional review board (IRB) to waive the regulatory requirement that individuals provide informed consent when enrolling in research studies. A requirement of the waiver of informed consent is that the reviewing IRB must review and approve a community consultation and public disclosure plan. It is critical that an IRB serving as the single IRB (sIRB) for multisite research be thoroughly versed in the local context concerns for each participating site to determine whether the site's community is being adequately consulted about the research in which individuals will be enrolled under an exception to the informed consent requirement. We designed an sIRB review model for evaluating site-specific community consultation plans that included a local evaluation and feedback step, and we piloted the model with a four-site, pediatric exception from informed consent (EFIC) clinical trial. We identified three key roles for the model: the sIRB, the investigators, and the representative of the institution's human research protection program (HRPP). We successfully collected the information and local input needed to evaluate each site's community consultation plan and applied the information to a thorough IRB review, despite the geographic distance between the study site and the sIRB.

Exception from informed consent trials: social-media-based community consultation campaigns are representative of target communities

Background‘Community consultation’ (CC) is a key step when conducting Exception From Informed Consent research. Social-media-based CC has been shown to reach more people than traditional methods, but it is unclear...

Multicenter social media community consultation for an exception from informed consent trial of the XStat device (PhoXStat trial).

Community consultation (CC) is a key step for exception from informed consent research. Using social media to conduct CC is becoming more widely accepted but has largely been conducted by single sites. We describe our experience of a social media-based CC for a multicenter clinical trial, coordinated by the lead clinical site. Multicenter CC was administered by the lead site and conducted in preparation for a three-site prehospital randomized clinical trial. We used Facebook and Instagram advertisements targeted to the population of interest. When "clicked," the advertisements directed individuals to study-specific websites, providing additional information and the opportunity to opt out. The lead institution and one other hospital relied on a single website, whereas the third center set up their own website. Site views were evaluated using Google analytics. The CC took 8 weeks to complete for each site. The advertisements were displayed 9.8 million times, reaching 332,081 individuals, of whom 1,576 viewed one of the study-specific websites. There were no requests to opt out. The total cost was $3,000. The costs per person reached were $1.88, $2.00, and $1.85 for each of the three sites. A number of site-specific issues (multiple languages, hosting of study-specific websites) were easily resolved. This study suggests that it is possible for one institution to conduct multiple, simultaneous, social media-based CC campaigns, on behalf of participating trial sites. Our results suggest that this social media CC model reaches many more potential subjects and is economical and more efficient than traditional methods. Epidemiological, level IV.

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

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. 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. 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. 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.

Study Enrollment When "Preconsent" Is Utilized for a Randomized Clinical Trial of Two Treatments for Acute Agitation in the Emergency Department.

Acute agitation in the emergency department (ED) represents a danger to both patients and their caregivers. Medication is often needed, and few high-quality randomized trials have evaluated the optimal drugs for this vulnerable population. In the United States, as of 2017, randomized trials of drugs typically cannot be conducted under Waiver of Consent (46 CFR 45.116), and Exception From Informed Consent trials (21 CFR 50.24) are limited to life-threatening conditions, are onerous, and require filing an investigational new drug application with the FDA. We sought to conduct a randomized double-dummy trial of inhaled loxapine versus intramuscular haloperidol + lorazepam for acute agitation in the ED by obtaining consent in advance ("preconsent") in patients at risk of future agitation, allowing study drug administration up to 3 years later if the patient presented with acute agitation. We sought to report the successful enrollment rate of patients preconsented at an earlier ED visit for this trial. This was an analysis of patients age 18 to 64 with bipolar I disorder or schizophrenia preconsented for enrollment in the trial (clinicaltrials.gov, NCT02877108) conducted at a single urban academic center seeing approximately 60,000 patients per year. Eligible patients were assessed for capacity to consent by trained research associates, and informed consent was obtained at an ED visit for the possibility of administering drugs for agitation within the next 3 years. In the event the patient later presented to the ED and the attending physician deemed the patient required treatment for acute agitation, preconsent was confirmed and study drug would be administered. Over 67 days, 1,461 patients were screened in the ED, 269 had bipolar I or schizophrenia, 194 of whom had a contraindication to inhaled loxapine leaving 75 eligible patients; preconsent was obtained in 43 patients. Four additional patients who had not preconsented were consented for the trial in real time (three by surrogate, one patient had capacity while agitated) resulting in a total of 47 consented patients. Of these 47, a total of 12 were later removed from the study: 10 patients had unrecognized exclusion criteria for inhaled loxapine, one preconsented patient contacted the investigators at a later date and asked to be removed, and one surrogate revoked consent immediately after providing it. Only two patients were successfully enrolled, neither by preconsent: one was enrolled via a surrogate the day of enrollment, and the other was mildly agitated and had capacity to consent. The remaining patient with a valid surrogate consent did not receive study medication. Utilization of preconsent to enroll patients in a randomized trial of treatments for acute agitation in the ED requires substantial resources and may not be feasible.

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

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. 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. 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. 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.

Using social media for community consultation and public disclosure in exception from informed consent trials.

The US Food and Drug Administration and the Department of Health and Human Services outline regulations allowing an exception from informed consent (EFIC) for research conducted in an emergency setting. Acute care clinical trials using EFIC must include community consultation and public disclosure (CC/PD) activities. We describe our experience using social media to facilitate the CC/PD process in two trauma resuscitation clinical trials. We conducted local CC/PD activities for two multicenter trauma clinical trials, Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) and Prehospital Tranexamic Acid Use for Traumatic Brain Injury (ROC-TXA). As part of the CC/PD process, we developed research study advertisements using the social media Web site Facebook. The Facebook advertisements directed users to a regional study Web site that contained trial information. We targeted the advertisements to specific demographic users, in specific geographic areas. We analyzed the data using descriptive statistics. During the study periods, the PROPPR Facebook advertisement was displayed 5,001,520 times (12 displays per target population) with 374 individuals selecting the advertisement. The ROC-TXA Facebook advertisement was displayed 3,806,448 times (8 per target population) with 790 individuals selecting the advertisement. Respondents to both Facebook advertisements were mostly male (52.6%), with the highest proportion between the ages 15 years and 24 years (28.2%). Collectively, 26.9% of individuals that clicked on the Facebook advertisement spent more than 3 minutes on the study Web site (3-49 minutes). Commonly accessed Web pages were "contact us" (PROPPR, 5.5%; ROC-TXA, 7.7%), "study-specific FAQs" (PROPPR, 2.4%; ROC-TXA, 6.7%), and "opt out of research" (PROPPR, 2.5%; ROC-TXA, 3.8%). Of 51 total individuals viewing the opt out of research information (PROPPR, 19; ROC-TXA, 32), time spent on that specific page was modest (PROPPR, 62 seconds; ROC-TXA, 55 seconds), with no individuals requesting to opt out of either study participation. In clinical trauma trials using EFIC, social media may provide a viable option for facilitating the CC/PD process.

Studying Community Consultation in Exception From Informed Consent Trials*

Studying Community Consultation in Exception From Informed Consent Trials*

Preliminary Experience With Social Media for Community Consultation and Public Disclosure in Exception From Informed Consent Trials

Each year in the United States, >300 000 individuals suffer cardiopulmonary arrest and >2 000 000 suffer a serious traumatic injury requiring hospitalization.1,2 Clinical advances in these fields have been limited because of the paucity of scientific evidence guiding resuscitation practices. Prospective clinical trials are important for advancing the knowledge base in these areas, but because of the emergent nature of these conditions and the inability of critically ill subjects to provide informed consent, investigators must often conduct clinical trials of cardiac arrest and trauma under federal regulations for Exception From Informed Consent (EFIC).3 Editorial see p 206 The US Department of Health and Human Services and the Food and Drug Administration have issued guidelines for the execution of clinical studies using the EFIC process.3 One of the key steps for EFIC research is community consultation and public disclosure (CC/PD), a process that connotes consultation between the investigative team, the appropriate institutional review boards, representatives of the communities where the research will be conducted, and communities likely to have the condition. However, the regulations provide little guidance on how to accomplish these key goals. Although traditional methods for CC/PD include public meetings and telephone-based surveys, the ability of these modalities to access the target populations, to effectively deliver information, and to elicit useful feedback remains unclear.4 Internet-based social media has emerged as a popular and powerful new modality for communication internationally. The objective of this study was to describe our preliminary experience using social media to facilitate the CC/PD process for cardiopulmonary arrest and trauma trials using EFIC. ### Study Design The activities for this study, including the use of social media for CC/PD, were approved by the Institutional Review Board of the University of Alabama at Birmingham. We devised a social media interface to facilitate the CC/PD process for …

Local Media Influence on Opting Out From an Exception From Informed Consent Trial

News media are used for community education and notification in exception from informed consent clinical trials, yet their effectiveness as an added safeguard in such research remains unknown. We assessed the number of callers requesting opt-out bracelets after each local media report and described the errors and content within each media report. We undertook a descriptive analysis of local media trial coverage (newspaper, television, radio, and Web log) and opt-out requests during a 41-month period at a single site participating in an exception from informed consent out-of-hospital trial. Two nontrial investigators independently assessed 41 content-based media variables (including background, trial information, graphics, errors, publication information, and assessment) with a standardized, semiqualitative data collection tool. Major errors were considered serious misrepresentation of the trial purpose or protocol, whereas minor errors included misinformation unlikely to mislead the lay reader about the trial. We plotted the temporal relationship between opt-out bracelet requests and media reports. Descriptive information about the news sources and the trial coverage are presented. We collected 39 trial-related media reports (33 newspaper, 1 television, 1 radio, and 4 blogs). There were 13 errors in 9 (23%) publications, 7 of which were major and 6 minor. Of 384 requests for 710 bracelets, 310 requests (80%) occurred within 4 days after trial media coverage. Graphic timeline representation of the data suggested a close association between media reports about the trial and requests for opt-out bracelets. According to results from a single site, local media coverage for an exception from informed consent clinical trial had a substantial portion of errors and appeared closely associated with opt-out requests.

A geospatial analysis of persons opting out of an exception from informed consent out-of-hospital clinical trial

For trials involving exception from informed consent, some IRBs require that community members be allowed to "opt out" prior to enrollment. We tested for geospatial clustering of opt-out requests and the associated census tract characteristics in one study region. This was a retrospective study at a single site of a multicenter exception from informed consent resuscitation trial. We collected and geocoded mailing addresses for persons requesting opt-out bracelets over 16 months, then tested for geospatial clustering using geographic information systems (GIS) analysis. Characteristics for tracts with and without bracelet clustering were compared using univariate tests, multivariable regression, and classification and regression tree (CART) analysis. We received 395 phone calls requesting 718 bracelets, of which 673 were analyzable. Of 397 census tracts in the region, 208 (52%) had at least one request and 38 (10%) demonstrated clustering. In multivariable models, an increasing proportion of family households (OR .90, 95%CI .85-.93), veterans (OR .91, 95%CI .81-1.02), and renters (OR .96, 95%CI .92-.99) were associated with lower odds of requesting an opt-out bracelet, while census tracts with higher income had higher odds of opting-out (OR 1.07, 95%CI 1.02-1.11). Using CART, the proportion of family households and graduate education identified the majority of opt-out requests by census tracts (cross-validation sensitivity 92%, specificity 56%). Opt-out requests for an exception from informed consent trial at one study site were geographically clustered and associated with certain population demographics. These findings may help identify key target groups for community consultation in future trials.

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

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). 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. 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. 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.