In the US, regulations on Exception From Informed Consent (EFIC) allow the study of treatments in emergent, life-threatening circumstances during which informed consent is not feasible.1 As part of EFIC requirements, researchers must complete “community consultation” defined as “the opportunity for discussions with, and soliciting opinions from, the community . . ..”2 A recent meta-analysis of community consultation surveys showed that most people were accepting of EFIC research, with 73% of respondents willing to be enrolled in the associated trial.4 However, as community consultation takes place prior to the initiation of the trial, these surveys must be considered hypothetical seeing as the participants had no risk of being enrolled at the time. Because the vast majority of EFIC studies take place in the pre-hospital and emergency room settings,5 the total number of patients at risk for enrollment and the proportion of those willing to participate are unknown. Therefore, we aimed to 1) compare the actual rate of willingness to participate with that from previously published hypothetical surveys conducted prior to the same trial; and 2) describe characteristics associated with willingness to participate in the trial. We hypothesized that the actual rate of willingness to participate would be lower than the hypothetical survey rate.
Epinephrine in the Pediatric Intensive Care Unit: A Dose-Effect Trial (EPI Dose) is a single-center, randomized, double-blind, dose-effect trial comparing two initial doses of peri-arrest bolus epinephrine for acute hypotension in the pediatric intensive care unit (PICU) (NCT05327556). The study has been approved by the local IRB (IRB-P00035730).
While contacting patients/families prior to the onset of a medical emergency is infeasible in most EFIC trials, the inpatient nature of our study provided a unique opportunity for the development of a novel process for meeting EFIC requirements which we have termed “personal public disclosure.” Personal public disclosure is part of a multi-pronged approach to meet the EFIC requirement for public disclosure, defined as the “dissemination of [study] information . . . sufficient to allow a reasonable assumption that the communities are aware of the plans for the investigation . . . and the fact that the study will be conducted [via EFIC].”2
Personal public disclosure is brief and distinct from informed consent, which remains infeasible given the high volume of at-risk PICU patients and the extreme rarity and unpredictability of the event of interest. Specifically, our research staff performs an in-person visit or phone call to the legally authorized representative for all eligible patients as soon as possible upon admission to the PICU. During this contact, the research staff member briefly describes the study and provides educational resources about the trial and the opportunity to opt out of future participation, if desired. As this procedure is part of our screening process, patients may not be enrolled prior to this discussion. Finally, as per EFIC regulations, we also train staff to provide an additional opportunity to object to participation and/or to contact the research team to obtain informed consent during the hypotensive event, if feasible; however, the latter is highly unlikely given the narrow therapeutic window for these events.
In the current (actual) cohort, we attempted to contact all eligible patients/families from April 13th to December 19th, 2023 while EPI Dose was actively enrolling. Patients were considered eligible if they were <26 years of age and admitted to a participating ICU. Patients who had limitations to resuscitation, were pregnant, breastfeeding, prisoners or wards of the state were excluded. Patients expected to be transferred or discharged from the ICU on the day of screening were not approached. Demographics were abstracted from the medical record, including race, ethnicity and language preference which are self-reported by the patient or guardian on admission.
For comparison, we used previously published data from surveys conducted for EPI Dose community consultation prior to commencement of the trial.6 Eligibility criteria and family education for this survey were similar the methods described above.6 After EPI Dose Trial information was provided, families were asked how likely they would be to allow their child to participate in the EPI Dose trial. Likert scale responses for willingness to participate were dichotomized, with families who answered that they would be “somewhat” or “very likely” to participate as willing to participate, and those who were “very unlikely,” “somewhat unlikely,” or “neither likely nor unlikely” categorized as opting out. Respondents reported their own race/ethnicity and language preference during the interview.
Descriptive statistics are presented as counts with relative frequencies, means with standard deviations or medians with interquartile ranges (IQRs), as appropriate. Fisher’s exact test was used to compare rates of willingness to participate between the actual and hypothetical cohorts. To compare patient characteristics between those willing to participate and those who opted out within the actual cohort, Wilcoxon rank sum and Fisher’s exact tests were performed as appropriate. Additionally, a post-hoc analysis was performed comparing willingness to participate rates among individual race/ethnicity categories using White race as the reference. P values <0.05 were considered significant.
For the actual cohort, 1716 patients were screened, 1591 (93%) were eligible for EPI Dose and 911 (53%) families were successfully contacted. Six patients were enrolled in EPI Dose, none of whom withdrew participation after post-enrollment notification. In the hypothetical cohort, 58 families participated. The baseline characteristics of the groups were similar (Supplemental Table 1). In the actual cohort, 609/911 (67%) patients/families were willing to participate in the EPI Dose trial compared to 43/58 (74%) in the hypothetical cohort (p = 0.31).
In the actual cohort, characteristics of patients willing to participate in EPI Dose were similar to those who opted out (Table 1). However, the method of contacting patients/families was associated with higher rates of willingness to participate for in-person visits (547/787 [70%]) compared to phone calls (55/115 [48%]; p <0.001). In the post-hoc analysis, families of Black/African/African American patients were less likely to be willing to participate than families of White patients (43/76 [57%] versus 272/394 [69%], RR 0.64; 95% CI, 0.43, 0.97; p = 0.045; Supplemental Table 2).
Table 1.
Characteristics of patients contacted during EPI Dose enrollment (actual cohort) by willingness to participate.
| Characteristics | Overall N=911 | Willing to Participate N=609 | Opted Out N=302 | p-value |
|---|---|---|---|---|
| Age in years, median (IQR) | 6 (1, 13) | 6 (1, 13) | 5 (1, 13) | 0.35 |
| Female sex | 364 (40) | 251 (41) | 113 (37) | 0.28 |
| Location | 0.88 | |||
| Medical ICU | 265 (29) | 176 (29) | 89 (29) | |
| Medical/Surgical ICU | 646 (71) | 433 (71) | 213 (71) | |
| Race/Ethnicity | 0.34 | |||
| Asian | 31 (3) | 19 (3) | 12 (4) | |
| Black, African American or African |
76 (8) | 43 (7) | 33 (11) | |
| Hispanic/Latinx | 154 (17) | 103 (17) | 51 (17) | |
| White | 394 (43) | 272 (45) | 122 (40) | |
| Other | 85 (9) | 54 (9) | 31 (10) | |
| Unknown | 171 (19) | 118 (19) | 53 (18) | |
| Preferred Language | 0.86 | |||
| Arabic | 28 (3) | 17 (3) | 11 (4) | |
| English | 724 (79) | 483 (79) | 241 (80) | |
| Spanish | 73 (8) | 52 (9) | 21 (7) | |
| Other/Unknown | 88 (10) | 58 (10) | 29 (10) | |
| Contact Method | N= 902 | N=602 | N=300 | <0.001 |
| In-person | 787 (87) | 547 (91) | 240 (80) | |
| By phone | 115 (13) | 55 (9) | 60 (20) |
Results presented as number (%) unless otherwise specified.
In this prospective cohort study, the actual rate of willingness to participate in an EFIC trial (67%) was not significantly different from the hypothetical rate in pre-trial survey data for the same trial (74%), contrary to our hypothesis. These findings are consistent with rates of acceptance for hypothetical enrollment amongst individuals surveyed as part of community consultation activities for other EFIC trials, which ranged from 64% to 85%.3,4 The distribution of race/ethnicity was similar in both the hypothetical and actual cohorts indicating that our pre-trial community consultation surveys accurately represented the population at risk for enrollment. This is important given recent findings from EFIC trials showing that Black people were under-represented in community consultation relative to the proportion who were enrolled.4
Patient characteristics for those willing to participate compared to those who opted out were similar; however, the post hoc analysis revealed families of Black patients were less likely to be willing to participate when compared to White patients. Racial and ethnic disparities in clinical trial enrollment are well-documented.7–9 Lack of diversity in clinical trials threatens the external validity of research findings, perpetuates health and healthcare disparities, leads to inadequate access to medical treatments, and undermines trust in the community.10 Despite the known downsides of lack of representation in clinical trials, there have been limited increases in the diversity of clinical trials over time.10 Many cite an unwillingness to participate, distrust of the medical system, and socioeconomic factors for the lack of diversity in clinical trials.9,10
Distrust may stem from a historical legacy of physical and medical abuse of racial and ethnic groups, while socioeconomic factors such as opportunity cost in time spent participating in a research trial may hinder diversity in clinical trial enrollment. However, data show that, if approached, racial and ethnic underrepresented groups are just as likely to participate in research as their white counterparts.10,11
Notably, our findings on race differ from prior studies, and this may be attributed to EFIC criteria and pediatric nature of the EPI Dose Trial. Given the current distrust of the medical community, parents from historically marginalized groups may be more distrustful of an interventional trial for their children in which informed consent is not performed. To enhance participation in clinical trials, particularly EFIC trials, the medical community should build a robust network of stakeholders to ensure diversity in the community consultation process, increase diversity in investigation teams, and continue to explore specific reasons for lack of willingness to enroll in EFIC trials.10
Another interesting finding is that in-person contact was associated with higher rates of actual willingness to participate compared to phone calls. This may indicate that face-to-face contact facilitates improved communication, comprehension and/or trust leading to families having more favorable opinions about the trial. Alternatively, this finding may be confounded by familial factors affecting their availability for in-person contact at the bedside, such as financial or social stressors that may also be associated with a lower willingness to participate in a clinical trial.
This study should be interpreted in the context of its limitations. First, data collection methods in the actual versus hypothetical cohorts differed. Second, there was a high proportion of missing data for race and ethnicity in the actual cohort, which may be informative. Additionally, we did not account for other social drivers of health in the race analysis. Finally, we did not collect data regarding reasons for why families chose to opt out of the trial.
In conclusion, the actual rate of willingness to participate in an EFIC trial in the PICU was similar to the hypothetical rate reported in pre-trial survey data, suggesting surveys drawn from a similar population may reasonably reflect attitudes of potential participants. Additionally, willingness rates varied by race. Future studies should explore parental barriers and willingness to participate in EFIC trials while working to build trust and incorporate diverse stakeholders in trial development and community consultation.
Supplementary Material
Supplemental Table 2. Relative risk of willingness to participate by race/ethnicity.
Supplemental Table 1. Patient characteristics in current (actual) cohort and historical (hypothetical) cohort.
ACKNOWLEDGEMENTS:
Dr. Ross’s work is supported by NHLBI: K23HL148312.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Grant money for investigator-initiated research: CER reports grant money to Boston Children’s Hospital to conduct research conceived and written by Catherine Ross, MD from NIH. MEK reports grant money to Boston Children’s Hospital to conduct research conceived and written by Monica Kleinman, MD from the Progeria Research Foundation.
Footnotes
Conflicts of interest:
No conflicts of interest: MA, HK, CG and RAB report no conflict of interest.
References:
- 1.U.S. Food and Drug Administration and Department of Health and Human Services. 21 CFR 50.24. Exception from informed consent requirements for emergency research. Federal Register 1996;61:51528. [Google Scholar]
- 2.U.S. Department of Health and Human Services, Food and Drug Administration, Office of Good Clinical Practice, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Center for Devices and Radiological Health. Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency Research. 2013. (https://www.fda.gov/downloads/Regulatoryinformation/Guidances/UCM249673.pdf). [Google Scholar]
- 3.Dickert NW, Metz K, Fetters MD, et al. Meeting unique requirements: Community consultation and public disclosure for research in emergency setting using exception from informed consent. Academic Emergency Medicine 2021;28(10):1183–1194. DOI: 10.1111/acem.14264. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Feldman WB, Hey SP, Franklin JM, Kesselheim AS. Public Approval of Exception From Informed Consent in Emergency Clinical Trials. JAMA Network Open 2019;2(7):e197591. DOI: 10.1001/jamanetworkopen.2019.7591. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Snyder KL, Merz JF. A census of clinical trials conducted under the U.S. exception from informed consent rule. Academic Emergency Medicine 2023;30(2):133–138. DOI: 10.1111/acem.14645. [DOI] [PubMed] [Google Scholar]
- 6.Ross CE, Lehmann S, Hayes MM, et al. Community consultation in the pediatric intensive care unit for an exception from informed consent Trial: A survey of patient caregivers. Resusc Plus 2023;13:100355. DOI: 10.1016/j.resplu.2022.100355. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Coakley M, Fadiran EO, Parrish LJ, Griffith RA, Weiss E, Carter C. Dialogues on Diversifying Clinical Trials: Successful Strategies for Engaging Women and Minorities in Clinical Trials. Journal of Women’s Health 2012;21(7):713–716. DOI: 10.1089/jwh.2012.3733. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Diversifying clinical trials. Nature Medicine 2018;24(12):1779–1779. DOI: 10.1038/s41591-018-0303-4. [DOI] [PubMed] [Google Scholar]
- 9.Winter SS, Page-Reeves JM, Page KA, et al. Inclusion of special populations in clinical research: important considerations and guidelines. J Clin Transl Res 2018;4(1):56–69. (In eng). [PMC free article] [PubMed] [Google Scholar]
- 10.National Academies of Sciences E, and Medicine. Improving Representation in Clinical Trials and Research: Building Research Equity for Women and Underrepresented Groups Washington, DC: The National Academies Press; 2022:280. [PubMed] [Google Scholar]
- 11.Hu WT, Bergren SM, Dychtwald DK, Ma Y, Dong X. Variations in racial and ethnic groups’ trust in researchers associated with willingness to participate in research. Humanities and Social Sciences Communications 2023;10(1). DOI: 10.1057/s41599-023-01960-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Table 2. Relative risk of willingness to participate by race/ethnicity.
Supplemental Table 1. Patient characteristics in current (actual) cohort and historical (hypothetical) cohort.