Clinical trials in the Intensive Care Units (ICUs) are among the most complex and demanding studies in clinical research. The scientific rationale for studying interventions in critically ill patients is compelling, but the operational reality is unlike almost any other clinical setting. Sponsors who approach the implementation of ICUs trials with a standard clinical trial playbook routinely encounter problems that could have been anticipated and planned for.
What makes critical care trials fundamentally different?
Several things converge at once:
- Consent- related barriers: Patients are acutely and severely ill, often unable to consent for themselves.
- Recruitment window: Many ICU trials operate within extremely narrow recruitment windows, meaning identification, consent and randomization must occur in rapid succession, often outside normal business hours.
- Patient and disease heterogeneity: Critical care syndromes exhibit enormous heterogeneity in etiology and severity, making it challenging to identify patients who will benefit from interventions versus those for whom therapy would be futile [1] [2]. For example, cardiogenic shock can result from numerous causes (ischemia, myocarditis, heart failure) with varying degrees of end-organ dysfunction [2]. This heterogeneity complicates trial design, sample size calculations, and interpretation of results [3].
- Resources limitations: Study procedures must integrate into a high-intensity care environment without disrupting it.
- Operational inefficiencies: Staff rotate across shifts, and no single investigator can carry the operational weight alone.
All the above factors contribute to low enrollment rates and frequent trial delays or failures.
This white paper sets out a practical operational framework for biotechs and pharma companies planning a clinical trial in an ICU setting, covering sites selection and feasibility; protocol designs; sites start-up and preparation for first patient in; management of ongoing patients; and long-term follow-up.
1. Sites Feasibility, Countries and Sites Selection
Sites selection for an ICU trial is a different exercise from sites selection in most other therapeutic areas. The goal is not just to identify the adequate investigators with relevant patient populations and GCP track records; but also, to pinpoint institutions in which the ICUs infrastructure, governance, and research culture can absorb the complex operational demands of a specific protocol.
An additional layer of complexity is the fact that critical care in a hospital occurs in multiple units, i.e. cardiac, neurological, neonatal, pediatric, and burns ICUs, and although some work procedures are common to all of them, each one operates with distinct patient populations, clinical workflows, and in some cases dedicated regulatory and ethical frameworks, and the protocol will only be feasible in one of them.
Getting this wrong at the feasibility stage is expensive; the problems that flow from a poorly suited site typically don’t surface until months after activation. One must build the planned enrollment models based on historical screen-to-enroll data at comparable sites, not only based on raw admission statistics. Patients´ volume is necessary but not sufficient. A site may admit large numbers of critically ill patients and still be operationally unsuitable.
Feasibility must probe realistic screening rates for the specific target population, accounting for eligibility criteria and the clinical window within which patients must be identified and enrolled.
For ICUs trials, Pivotal evaluates sites across a set of critical domains:
- Patients´ population and recruitment potential: The site must have sufficient patient flow matching the specific target condition, not just general ICU volume.
- Strong engagement of ICU PIs and Teams: The principal investigator’s (PI) operational commitment is the most consequential variable in an ICU site performance, and the hardest to assess solely based on a questionnaire. The PI must be operationally committed, driving accountability within the team, and ensuring study priorities are embedded in the ICU’s working culture. Early engagement with PIs and the broader ICU team before the feasibility questionnaire is even issued, is not a courtesy; it is an operational necessity. These conversations surface constraints that no questionnaire will capture. ICU teams feedback is essential to refine patients´ identification strategies and to understand how study activities can be realistically integrated into routine care.
- Capacity for 24/7 screening and enrollment: Eligible patients do not present on schedule. Sites must demonstrate genuine round-the-clock recruitment capability with sufficient staff to maintain coverage across shifts. Sponsors should be aware that out-of-hours enrollment is significantly more constrained in some geographies than others.
- ICU staff: ICU-based clinical trials demand a highly trained team of dedicated research nurses and study coordinators who can ensure round-the-clock (24/7) coverage, given the critical nature of the patients and the time-sensitive study procedures.
- IMP: Mechanisms must be organized to allow for the preparation, release and administration of the investigational medicinal product (IMP) around the clock.
- Infrastructure and equipment readiness: Equipment-dependent assessments can become enrollment bottlenecks if the required equipment is not available 24/7. A single assessment that cannot be completed on time can render a patient unevaluable for the primary endpoint, regardless of how well everything else was managed. IMP storage is equally critical: sites relying solely on a central pharmacy that closes overnight may not meet tight dosing timelines. A secure, temperature-monitored storage location within or immediately adjacent to the ICU should be evaluated and secured during feasibility, not after activation.
- Surrogate or deferred consent experience: The majority of critically ill patients (>90%) lack capacity to provide informed consent, requiring surrogate decision-makers (SDMs) who may be unavailable, difficult to contact, or entirely absent [4] [5] [6]. In one multicenter study, 57.3% of recruitment opportunities were missed or unfeasible, largely due to research team workload, limited availability, narrow time windows, and difficulties contacting families [6]. The unavailability of a legal proxy within short enrollment windows was identified as the major impediment to enrollment, accounting for 88% of missed opportunities in one trial [7].
Research ethics committees often show reluctance to approve alternative consent models such as deferred consent or research without prior consent, despite their potential benefits in time-sensitive studies [5]. Canadian ICU trials using alternate or hybrid consent models achieved consent rates of 78-100% compared to 54-91% for trials using only prior informed consent [8]. Consent pathways vary widely across countries.
These requirements must guide early countries and sites selection. A site-facing surrogate or deferred consent for the first time during live enrollment creates avoidable operational risk.
2. Protocol design
Platform trials and adaptive designs offer substantial advantages for critical care research including increased efficiency, faster answers, reduced sample sizes, and the ability to test multiple interventions simultaneously. These designs directly address many of the recruitment and retention challenges inherent to ICU trials.
Platform trials are randomized clinical trials that allow multiple interventions to be simultaneously evaluated and new interventions to be added after the trial is initiated. The platform provides a single infrastructure wherein interventions can be added and discontinued at different time points after their clinical questions have been answered through comparisons against a control group, sometimes shared across interventions.
Unlike conventional RCTs (Randomized Clinical Trials) with fixed sample sizes and defined endpoints, platform trials are designed to continue for longer durations to enable multiple interventions to be evaluated at different time points [9].
These trials operate under a master protocol, one overarching protocol with standardized operating procedures for all interventions and the control group. The master protocol is structured in a modular format with intervention-specific appendixes that can be added without updating the entire protocol, expediting the addition of new interventions and streamlining institutional ethical review.
During the COVID-19 pandemic, REMAP-CAP and RECOVERY demonstrated the success of adaptive platform trials [10]. Both studies used master protocols governing overarching features including entry criteria, data collection, and outcome ascertainment with a modular structure for questions about individual interventions. These platform trials were designed to be embedded within clinical care, of low burden to the clinical team, and linked directly to patients´ clinical care decisions.
Traditional study designs typically test one intervention at a time, which is inefficient especially for diseases requiring multicomponent care regimens. In contrast, these platform trials tested multiple components of a patient’s clinical care regimen simultaneously.
Another example of platform trials is The Intensive Care Platform Trial (INCEPT), an investigator-initiated, pragmatic, randomized, embedded, multifactorial, international, adaptive platform trial including adults acutely admitted to ICUs [11].
Adaptive clinical trial designs facilitate the evaluation of several candidate treatments simultaneously, learn from emergent discoveries during the course of a specific clinical trial, and can be structured efficiently to lead to more timely conclusions compared to traditional trial designs [12]. The goal is to provide flexibility such that a trial can serve as a definitive test of its primary hypothesis, preferably in a shorter period of time, involving fewer subjects, and at a lower cost [13].
However, these types of trials also present conflicting points regarding operational complexity, statistical and methodological considerations and infrastructure requirements [14] [15].
3. Sites Start-up and the Lead-Up to First Patient In (FPI)
Site start-up in an ICU trial carries a higher cost of inadequate preparation than in most other settings. The conventional start-up sequence (regulatory submissions, SIV, pharmacy set-up, training) must be extended to cover the specific operational conditions that will govern enrollment in an ICU setting. Getting a site initiated is only part of the challenge; getting it genuinely ready to recruit the target patients in a way that actively operates, e.g. at 2 am, requires a different kind of preparation.
Site Initiation Framework
To ensure proper sites initiation, Pivotal set up a comprehensive initiation framework:
- Run simulations before the first patient is approached: Before FPI, a simulation mock visit must be successfully tested. Mock screening exercises and simulated consent discussions allow teams to rehearse the full recruitment sequence under realistic conditions. They surface logistical problems before they impact a real patient: a pharmacy that cannot dispense out-of-hours, an eligibility criterion that is ambiguous in practice, and many others. This is not common in standard trials, but in the ICU, it is a meaningful risk mitigation tool.
- Fully operationalize consent pathway: The consent pathway must be end-to-end operational before FPI — not agreed in principle, not described in a process document, but rehearsed, tested, and confirmed as executable at every hour of the day. Each site needs a documented, site-specific consent plan covering every detail: who identifies the patient as potentially eligible, who makes the decision to initiate the consent process, who contacts the legal representative or next of kin, what happens when no representative can be reached within the eligibility window, and how the initial consent documentation is completed and filed.
Staff must be trained to navigate these pathways efficiently. When electronic consent solutions are used for remote representative consent, the process must be tested before the site goes live.
- Build staffing plans and coverage rotations at sites initiation: Research coordinator experience and availability are critical determinants of recruitment success. Greater coordinator experience and higher site research volume significantly predict fewer declined consents [6]. The staffing plan for an ICU trial must be built at initiation and documented before the first patient is enrolled — not assembled informally as the study gets underway. Every site should enter the live phase with a documented coverage plan: who is responsible for study procedures on each shift, who is the backup, and how handovers are managed. The PI should act as the operational lead, but no trial should depend on any single individual being available.
- Design training for high-turnover environments: ICU staff rotate frequently. Training must be designed from the outset for this environment, not retrofitted when the first gap emerges. This means building a training infrastructure rather than a training event, i.e., a concise study procedure card laminated, unit-specific, covering the three or four actions most likely to be needed at short notice, is more reliably consulted at 2 am than a 40-slide training deck. Training materials should be modular, accessible and include recorded sessions that new team members can work through independently. The ability to onboard new staff rapidly without disrupting ongoing recruitment is a meaningful operational advantage.
- Resolve all IMP procedures before enrollment begins: IMP access in an emergency or time-critical setting presents logistical challenges that must be resolved before, not after FPI. If a specific protocol requires IMP administration within four hours of diagnosis, the IMP must be physically accessible within that time window, which may mean satellite storage within the ICU, a pre-dispensing model, or a specific out-of-hours pharmacy agreement. Temperature excursion management also deserves specific attention.
ICU environments, particularly around patient transport and procedure rooms, create real risk of inadvertent storage condition violations. The pharmacy, the research coordinator, and the clinical team must have a shared, documented escalation pathway for excursion events. None of these issues should be left to be worked out when a situation arises.
4. Managing Ongoing Enrolled Patients: Pharmacy, Data and Safety
Managing enrolled patients in an ICU trial is an exercise in adaptation. Some features which complicate still further enrollment in an ICU clinical trial are: high mortality and dropout rates, clinical deterioration and complications related to specific procedures such as catheters, intubation, complex vascular access and others. Once patients start enrolling, the challenge shifts to maintaining quality and oversight in an ever-moving environment that does not stand still.
Proactive Monitoring
- Monitor proactively IMP administration timelines: If not actively tracked, IMP administration timelines are among the highest-risk data points in the study, and among the most likely to generate eligibility-affecting deviations. Active monitoring of the IMP administration timelines provides early visibility of site-level operational practical problems before they accumulate into a pattern that compromises the dataset. Many ICU trials specify that first dose must occur within a short time window period after randomization. This requires that the IMP is stored and prepared close to the point of care, with no dependencies on systems or personnel unavailable out-of-hours. Administration timelines must be tracked as a key performance indicator throughout the trial.
- Design a 24/7 support model that is efficient, not just available: A well-designed on-call system with a primary contact, a clear escalation pathway and no voicemail barriers can provide effective coverage without requiring a large team on permanent standby. The site team operating at 3 am performing an urgent consent or posing an IMP administration question needs to reach someone with protocol-specific knowledge and decision-making authority, not a holding message and a promise to respond on the next business day.
- Use pre-screening logs to manage recruitment in real time: A well-maintained pre-screening log provides wealth of information about the reasons for non-enrollment which are visible and actionable. Although it may pose an extra workload on the site´s team, recording all patients presenting with the target condition, not just those screened or enrolled, creates visibility into where opportunities are being lost. A site identifying patients but failing to enroll them may likely have a consent or workflow problem. Acting on this hurdle early is far more effective than waiting for trends to become apparent in overall figures. At Pivotal, we review pre-screening data regularly with site teams to ensure issues are identified and addressed before they impact recruitment.
- Calibrate safety reporting to the ICU population: SAEs reporting in the ICU presents a definitional challenge that has no clear parallel in most other therapeutic areas. The critically ill patient is, by definition, in a serious condition. The distinction between an expected progression of an underlying illness and an unexpected adverse event attributable to the study intervention requires sound clinical judgement that most sites find genuinely difficult to apply consistently. A practical solution is to pre-define common events that are captured on a dedicated eCRF page for aggregate review rather than individual AEs reporting, reducing site burden without compromising safety events tracking. This should be agreed upon with the relevant authorities and documented in the protocol.
- Build the EDC around the ICU environment: Data is generated quickly, from multiple sources, by staff primarily focused on the evolving patient clinical care. The data entry workflow must map out to the clinical team’s documentation rhythm, not impose a separate parallel process.
EDC Configuration
At Pivotal, we design our EDC configurations specifically for this setting, applying the following principles:
- Build in edit checks that catch the specific error patterns common in ICU documentation.
- Programmed edit checks reserved for critical data points only: eligibility, dosing, safety and primary endpoints.
- Non-critical discrepancies reviewed in batch, not flagged in real time.
- Query resolution coordinated with monitoring visits to reduce back-and-forth communication.
- Derived fields, dropdowns, and auto-populated values to reduce entry errors.
Match monitoring intensity to the phase of the trial. Oversight should be at its highest level during the acute treatment period and taper appropriately as the patient moves into follow-up. Monitoring intensity should also respond to signals during the trial. Risk-based monitoring in ICU trials must be dynamic, not fixed. The risk profile of an active ICU trial shifts materially across its lifecycle, and the monitoring plan should reflect this rather than applying a uniform visit cadence from activation to close-out.
5. Long-Term Follow-Up
Short-term follow-up is usually manageable since most patients remain hospitalized at the primary endpoint timepoint; the key risk is early discharges, which can be mitigated by proactive communication and clear expectations before patients leave the hospital.
Long-term follow-up (FUP) in ICU trials presents a set
