Initial steps

In 2022, researchers at the University of Rochester were invited to join a randomized clinical trial to evaluate the pharmacokinetics of a new preparation of a commonly used antiseizure medication and investigate the efficacy of two different dosages in infants. The study was approved by faculty in the Division of Neonatology and the Institutional Review Board. Neonatal providers were assured that all subjects would receive treatment, and the difference between treatment arms was the dosage of the medication.

During discussions regarding study logistics among the investigators and the study coordinator, it became clear that the timeline for identifying, consenting, and enrolling study participants, as well as for initiating the study drug, was very short and involved the close and effective coordination of several different stakeholder groups. Given the subject population and the clinical diagnosis, the individuals needed to successfully carry out all study procedures would have to be readily available at any time. Thus, a small team consisting of a neonatologist with expertise in neonatal neurology and conducting clinical trials, the research coordinator, and a neonatologist with expertise in utilizing simulation for education, quality improvement, and research carefully reviewed the study protocol, familiarized themselves with all aspects of the trial, and planned simulations to identify barriers to success.

Identification of stakeholders and roles

For this particular study, different stakeholder groups with specific roles would need to coordinate with each other to help ensure a smooth workflow within the constraints of a tight timeline to identify and enroll potential high-risk infants before they exhibit electrographic seizure activity. In addition to the core research team (site principal investigator, co-investigators, and site coordinator) who would be overseeing the study and the neonatal intensive care unit (NICU) clinical team (physicians, nurses, and other staff) who would be providing routine care to the infant, we identified several services that would have key roles, including child neurology, electroencephalography (EEG) (technicians and certified EEG interpreters), and the investigational drug service (IDS) with the help of pediatric pharmacy.

As part of study procedures, the clinical team identifies neonates likely eligible for the trial and contacts the core research team. The study coordinator or site investigator then reviews the medical record to assess eligibility and obtain permission from the infant’s clinical team to approach the family to introduce the study. During the time the family considers whether or not to participate, the research team notifies the child neurology and EEG teams that there is a potential study participant who, if the parents consented, would need a qualifying EEG to be performed and interpreted. After consent, while preparations for the EEG are underway, the research team contacts IDS to begin preparing the two dosages of the study drug in the event the EEG interpretation indicates that the infant is eligible for study participation. Once eligibility is confirmed by EEG, the research team randomizes the infant to identify which dosage of the study drug the infant would receive. The research team also communicates with the clinical team about pertinent study procedures, including instructions on how to administer the study drug and which laboratory studies to obtain. A qualified examiner performs physical exams and records findings at predetermined intervals. Throughout this process, the research team provides oversight and guidance.

Development of scenarios

To identify the potential major issues of conducting this study in situations of varying complexity, we designed two simulation scenarios with different infant diagnoses, clinical presentations, timing of seizure activity, and availability of research stakeholders (Supplementary Material 1). We iteratively reviewed and revised the scenarios with input from an additional neonatologist and neurologist to consider conditions that would optimize our ability to uncover challenges.

The goal of the first scenario was to provide participants the opportunity to identify potential issues from subject identification, consent, and enrollment to the initiation of study procedures in a relatively straightforward situation. To allow participants to focus first on basic steps, the scenario occurred during daytime work hours, which eliminated the complexities inherent in off-hour communications. The scenario consisted of a newborn infant who was born on a weekday morning and diagnosed with hypoxic ischemic encephalopathy (HIE). We chose this diagnosis because approximately half of infants with HIE develop clinically apparent seizures at 12–24 hours of age [Reference Shellhaas, de Vries and Glass12,Reference Ziobro and Shellhaas13] and are anticipated to constitute at least half of the study subjects. In this clinical scenario, the occurrence of seizures can be anticipated, and there would be adequate time to speak with parents and communicate with all stakeholders.

The second scenario involved more complexity, building on the lessons learned from debriefing the events of the first simulation. This scenario included a shorter timeline for enrollment and study initiation, as well as an off-hour diagnosis of neonatal seizures to identify issues specific to the performance of study procedures at night or during the weekend. The infant in this scenario unexpectedly presented with seizure-like activity, which was likely due to intracranial hemorrhage or meningitis as the next most common etiologies of seizures in this age group [Reference Shellhaas, de Vries and Glass12,Reference Ziobro and Shellhaas13]. Given the unexpected onset of symptoms and the usual practice of initiating treatment as soon as possible, either following confirmation of electrographic seizures by EEG or more quickly if physiologically destabilizing clinical seizures occurred, the notification of research team members had to be more immediate such that screening, approach, consent, and randomization did not interfere with clinical standard of care.

Identification of challenges with team-based simulations and debriefings

Individuals representing each of the stakeholder groups were invited to participate in a team-based simulation and debriefing session. Before participation, participants received an email that oriented them to the purpose of the simulation sessions. They also reviewed and had an opportunity to ask clarifying questions about the research protocol.

The simulations were conducted with a moderate-to-high level of fidelity, mirroring as much as possible what would occur in a real clinical situation to achieve the goals and objectives of examining the complex interactions of different stakeholders involved in this study. Because of our focus, it was important that we conducted the simulations in situ, in a patient room in the neonatal intensive care unit, with individuals responsible for clinical care and for all study procedures. Participants were instructed to interact with the infant mannequin, utilize computer interfaces, and communicate with each other as they normally would (e.g., face-to-face, text messaging, and web paging). Most parts of the scenario unfolded in real time to gauge the amount of time it would take to accomplish specific tasks. However, for some tasks that would take a longer period of time to complete (e.g., placement of EEG leads and preparation of the different dosages of study drug), participants estimated the length of time based on prior experiences of patient care and/or during clinical trials so that the simulation would proceed more efficiently. Since the simulation was not focused on the procedures themselves but rather on efficient communication among the various services, and performing all the individual steps would require an additional 1–2 hours, we felt this “short cut” was appropriate. For clinical trials that include novel procedures, such procedures can be incorporated into the simulation.

After a 10–15-minute orientation over videoconferencing to review the purpose of the session, the simulation commenced with in-person participation. Individuals representing each stakeholder group were drawn into the scenario at different times based on their specific roles. All participants and the simulation team took notes and jotted observations and questions that required clarification and discussion. Each simulation was conducted over approximately 60–90 minutes, followed by an additional 60 minutes for debriefing simulation events. The simulation team utilized a checklist comprised of anticipated scenario activities (Supplementary Material 2) to facilitate a semi-structured team debriefing, during which participants identified aspects of the simulation that occurred fairly smoothly, as well as obstacles that needed to be addressed. After each session, the core research team and simulation facilitator discussed findings, sought solutions to potential problems, and decided what materials had to be developed prior to initiation of the study. Audio recordings and/or detailed notes of all discussion points during the debriefing and post-debriefing discussions were compiled for reference and thematically categorized. An overview of the entire process is depicted in Figure 1.

Figure 1.

Overall depiction of the steps in developing, performing, and debriefing simulations prior to the initiation of complex clinical trials.