Personal Public Disclosure: A New Paradigm for Meeting Regulatory Requirements Under Exception From Informed Consent

Abstract

Objective:

To describe a novel approach to the requirement for public disclosure under regulations for Exception From Informed Consent (EFIC) in an inpatient clinical trial.

Design:

Single-arm intervention study within a clinical trial.

Setting:

Medical and medical/surgical intensive care units (ICU) at an academic children’s hospital.

Participants:

Families of children and young adults <26 years of age receiving care in an ICU.

Interventions:

As part of a multi-pronged approach to meeting requirements for public disclosure for EFIC, we developed and implemented a process termed “personal public disclosure” in which a member of the study team notifies all potentially eligible patients/families in-person or by phone about the trial as soon as possible upon ICU admission. Patients/families may choose to opt out of future participation in the trial.

Measurements and Main Results:

Over a 16-month period, 1577 potentially eligible patients/families were successfully contacted for personal public disclosure. Of these, 473 (30%) opted out of future participation in the trial. In the same period, 64 patients developed the emergent event of interest for the primary trial. Of these, only 9 (14%) were enrolled. Upon notification of enrollment, all 9 (100%) agreed to continue in the data collection phase of the study. Of the remaining 55 missed enrollments, 38 (69%) were due to the event occurring before personal public disclosure had been completed.

Conclusions:

Personal public disclosure supports patient/family autonomy within an EFIC trial, however, this approach is limited by low cost-effectiveness, feasibility and appropriateness in many circumstances.

INTRODUCTION:

Regulations on Exception From Informed Consent (EFIC) in the US allow trial interventions to be performed during life-threatening emergencies when traditional informed consent is not feasible. EFIC regulations attempt to balance the need for emergency interventional research with the protection of vulnerable patient populations by placing additional responsibilities on investigators, including the requirement for public disclosure. Public disclosure for EFIC is defined as the “dissemination of information about the emergency research sufficient to allow a reasonable assumption that the communities are aware of the plans for the investigation, its risks and expected benefits, and the fact that the study will be conducted without obtaining informed consent for most or even all subjects” (1). However, there are no specific guidelines on how to fulfill these requirements, and published data suggests that the effectiveness of public disclosure methods in reaching the patients who go on to be enrolled in EFIC studies is extremely limited (2). Therefore, we leveraged the unique opportunity provided by our inpatient EFIC trial to develop and implement a novel method for public disclosure.

MATERIALS AND METHODS:

Parent Trial:

Epinephrine in the Pediatric Intensive Care Unit: A Dose-Effect Trial (EPI Dose) is a single-center, prospective, randomized, double-blind, dose-effect trial comparing two initial doses of peri-arrest bolus epinephrine for acute, life-threatening hypotension in the Pediatric Intensive Care Unit (PICU; NCT05327556). Eligibility criteria have been described previously (3). EPI Dose qualifies for use of EFIC based on the following factors: 1) the number of potentially eligible patients admitted to our PICUs far exceeds what is reasonably achievable for obtaining informed consent (estimated 2500 per year); 2) the extreme rarity of eligible hypotensive events within this population (estimated 40 per year); 3) the inability to predict those patients at highest risk for a hypotensive event far enough in advance to obtain informed consent; and 4) the time from onset of acute hypotension to need for intervention (“therapeutic window”) is insufficient for obtaining informed consent. Based on this rationale, the EPI Dose protocol (including the current study’s procedures) was approved by our Institutional Review Board (IRB) on April 11^th, 2022 (IRB-P00035730) and issued Investigational New Drug status from the Food and Drug Administration (FDA) which is required for all studies utilizing EFIC. Procedures were followed in accordance with the ethical standards of the IRB and with the Helsinki Declaration of 1975.

Approach:

As part of a multi-pronged approach to public disclosure, we developed a process which we have termed “personal public disclosure,” in which a member of our research team notifies all potentially eligible patients (if ≥18 years old and competent for medical decision making) or their families (all others) about the EPI Dose Trial as soon as possible upon PICU admission. First, our research team checks with the bedside nurse to identify the optimal timing for approaching the family with respect to their emotional state. When appropriate, our research staff member personally contacts families at the bedside or by phone and briefly describes the study, provides educational materials (flier, website URL), answers questions and offers the opportunity to opt out of future participation (Supplement). All contact attempts and resultant decisions about opting out are recorded for tracking. Patients expected to be transferred or discharged from the PICU on the day of screening are not approached.

If the patient/family chooses not to opt out, standard hospital signage in the patient’s room is labeled with a study sticker to identify eligibility. This signifies to the clinical staff that the patient may be enrolled if they go on to experience acute hypotension. As personal public disclosure is part of our screening process, patients may not be enrolled prior to this contact. Once a patient is enrolled, we notify the patient or legal guardian of their participation as soon as possible after the patient is stabilized, as is required by EFIC regulations.

Rationale:

The rationale for developing personal public disclosure included several factors. First, given the inpatient nature of the study, we felt that more targeted public disclosure methods would be beneficial due to established relationships with clinical care teams. Direct contact with families ensures basic knowledge of the study prior to enrollment, and the opportunity to opt out supports patient/family autonomy and voluntariness, in turn promoting transparency and trust in our institution. Second, there is precedent for direct family contact during an EFIC pilot trial in the pediatric ICU (4). Third, direct contact may lead to reduced parental anxiety and higher willingness to participate in the study compared to passive forms of public disclosure (i.e. posters or fliers) by enhancing communication between the family and research staff (4, 5). Finally, personal public disclosure aligns with our screening process which relies on the research team to label potentially eligible patients’ room signage with a study sticker; logistically, it follows that we provide families with study information prior to this labeling.

At face value, direct contact with patients/families may be viewed by some as an opportunity to obtain informed consent and thus negate the need for EFIC. However, informed consent in EPI Dose remains infeasible for the reasons stated above, independent of our approach to public disclosure. Because informed consent requires investigators to provide the potential participant with highly detailed information and adequate time to consider whether to participate, the process often takes 30 minutes or more. Conversely, the goal of personal public disclosure is narrower and thus entails the provision of only basic study information. This process requires approximately 5 minutes for most visits, and families may independently review additional study information via the flier or website afterward. Table 1 describes additional distinctions between personal public disclosure and informed consent.

Table 1.

Distinctions between personal public disclosure and informed consent.

	Personal Public Disclosure	Informed Consent
Approximate Visit Time	5 minutes	30 minutes
Context	General terms: “There is a study occurring in the ICU.”	Specific to the patient: “If you agree and your child qualifies, we will enroll your child in this study”
Level of detail	Basic overview	High level details
Materials	1-page flier, mostly infographics; left with the family for future reading	12-page consent form; reviewed in detail with the study team at time of visit
Goal of interaction as per FDA guidance documents1,5	“provide sufficient information to allow a reasonable assumption that the broader community is aware of the plans for the investigation, its risks and expected benefits . . . and the fact that the study will be conducted without obtaining informed consent from most study subjects.”	“providing a potential subject with adequate information to allow for an informed decision about participation in the clinical investigation, facilitating the potential subject’s comprehension of the information, providing adequate opportunity for the potential subject to ask questions and to consider whether to participate, obtaining the potential subject’s voluntary agreement to participate . . .”
Required clinical trial documentation	Patient records must be collected only for enrolled patients who receive the trial intervention.	Basic patient records must be collected for all who provide informed consent, regardless of receiving the trial intervention.

RESULTS:

From February 1st, 2023 to May 23rd, 2024, 2781 patients were screened, of whom 2439 (88%) were found to be potentially eligible for EPI Dose. Of the 1577 (65%) patients/families who were successfully contacted, 473 (30%) opted out after personal public disclosure. No patients opted out via the study website or phone line. In the same period, 64 eligible patients developed acute hypotension requiring bolus epinephrine. Of these, only 9 (14%) were enrolled in EPI Dose. Upon notification of enrollment, no families expressed surprise or negative reactions toward being enrolled, and all agreed to continue in the data collection phase of the study. Of the remaining 55 missed enrollments, 38 (69%) were due to the event occurring before personal public disclosure had been completed.

DISCUSSION:

In this single-arm interventional study, we describe the use of personal public disclosure during an inpatient EFIC trial. We report an opt out rate consistent with previous findings (3), as well as a significant number of missed enrollments attributable to the requirement for personal public disclosure as part of our screening process.

While personal public disclosure affords many patient/family-centered benefits as described above, our data reveal that this approach has significant limitations and may not be appropriate or feasible for all inpatient EFIC studies. Most notably, the requirement for direct contact prior to enrollment in our study significantly limited our ability to enroll patients who develop hypotension early in their PICU course, particularly if they are admitted during off hours. While extending screening hours may help to mitigate this issue, we anticipate that many families would not be open to discussing research in the late hours of the night, especially if their child remains tenuous upon admission. Given these limitations, we chose to focus efforts on staff education and logistics to ensure maximum enrollment of screened/eligible patients.

Additionally, personal public disclosure is time-intensive and costly. In order to optimize enrollments by visiting families as early as possible after admission, we employ 2 full-time research assistants to cover 13 hours per day, 6 days per week. Relative to the number of enrollments, this is not particularly cost-effective. Therefore, careful consideration of the ratio of at-risk patients to those who go on to meet eligibility criteria should drive the need for personal public disclosure. Events that are extremely rare, such as extracorporeal cardiopulmonary resuscitation (ECPR), for example, may not warrant such extensive public disclosure methods, nor would personal public disclosure be feasible if the entire population of hospitalized patients were considered to be at-risk.

Additional considerations for public familiarity with the medical emergency or intervention may also play a role in the decision to utilize personal public disclosure in an EFIC trial. In the case of EPI Dose, both the condition (hypotension) and the intervention (epinephrine) were easily understood by families after only a basic explanation in our pre-trial surveys (similar to that used for personal public disclosure; Supplement) (6). Additionally, we previously reported that many families were familiar with epinephrine as a treatment for anaphylaxis, and this familiarity was qualitatively associated with willingness to participate in the trial (6). In contrast, a study of ECPR, for example, involves a rare and complex intervention, and thus would require significantly more explanation. Furthermore, the immediate risk of death from cardiac arrest is much greater than that for hypotension (though this is explicitly stated during personal public disclosure). Therefore, we speculate that attempts to provide personal public disclosure in this case would cause significant confusion and anxiety for families, especially considering the very low proportion of patients who go on to receive ECPR. Future research should explore this concept.

The major strengths of this study include a large sample size and the prospective collection of opt out and enrollment data. Our major limitation is that this was a single center experience, and the findings may not be generalizable outside the context of the EPI Dose Trial design.

CONCLUSIONS:

In conclusion, we outline a novel approach to meeting requirements for public disclosure for inpatient EFIC studies characterized by direct contact with families of potentially eligible patients prior to the onset of the medical emergency. While this approach offers additional protections for vulnerable patients, its use is limited by low cost-effectiveness, feasibility and appropriateness in many circumstances.

Key Points:

Question:

Can direct contact with patients/families serve as a method for public disclosure in an inpatient Exception From Informed Consent (EFIC) trial?

Findings:

In this single-arm interventional study, 30% of potentially eligible patients/families opted out of future participation in the trial. In the same period, only 14% of patients who went on to experience the medical emergency of interest were enrolled in the trial, predominantly because they had not been contacted prior to the event.

Meaning:

While personal public disclosure provides added protections during an inpatient EFIC trial, the approach is limited in terms of cost-effectiveness, feasibility and appropriateness for some studies.