Conducting multicenter clinical research is challenging, particularly when the intervention has a short therapeutic window and is implemented in critically ill children who have experienced an unanticipated, life-threatening event. Administrative challenges (multiple Institutional Review Board [IRB] approvals, subcontracts, and training), scientific challenges (equipoise and standardizing protocols among various centers) and financial challenges are common in multi-site trials (1
). These are compounded when pediatric researchers must identify eligible research subjects from smaller pediatric patient pools compared with adult trials, address complex issues of parental consent and child assent (3
), tackle the perceptions and lack of understanding among parents and pediatric healthcare providers about research with children (5
), manage the range of IRB assessments of trial risks and benefits (4
), and procure the requisite expertise and additional funds needed to perform study interventions and long-term follow-up in children (10
). Strategies have been identified for simplifying research processes, streamlining activities and decreasing the often-excessive time required to complete a trial (11
), yet investigators continue to struggle to complete recruitment on time and within the budget allotted (15
). Given the hurdles for complex pediatric trials, implementing strategies and practices that can enhance trial success is paramount.
One potential strategy is a vanguard phase, sometimes referred to as a pilot or run-in phase. Vanguards have been used to assess the safety of an intervention, to determine the feasibility of a trial, or establish the ability of a study to meet treatment or recruitment goals. Although logistics and inclusion/exclusion criteria are usually considered finalized when protocols are completed, vanguards offer the opportunity to re-examine these in a real world setting and make proper adjustments prior to launching the main trial, thereby increasing the likelihood of trial success (17
In 2000, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, funded by the National Heart, Lung, and Blood Institute (NHLBI), used a vanguard phase to determine recruitment and treatment feasibility. Recruitment of 1174 subjects in 20 weeks exceeded the target goal of 1000, demonstrating feasibility. The successful vanguard recruitment strategies identified permitted the main trial to complete target enrollment of 10,000 subjects within 3 months of the planned date (18
). The vanguard phase also facilitated site preparedness and identified protocol modifications that enhanced study feasibility (19
In 2007, investigators for the Therapeutic Hypothermia after Pediatric Cardiac Arrest (THAPCA) trials approached the NHLBI to request permission to submit an application for a 30-site randomized clinical trial. Based on prior cooling studies that demonstrated improved functional survival in adults after cardiac arrest and in preterm infants with birth asphyxia (20
), THAPCA would test the hypothesis that therapeutic hypothermia versus therapeutic normothermia would improve survival and neurobehavioral outcomes after cardiac arrest in two separate clinical trials: in-hospital (IH) and out-of-hospital (OH).
Why a Vanguard Phase?
NIH peer review reflected enthusiasm for THAPCA and the potential for understanding optimal pediatric temperature management that might lead to improved outcomes, given the limited therapeutic options available. The NHLBI Advisory Council, the second level of review for all proposed grants, also recognized the importance of answering this question. However, there were concerns about the proposed costs and complexities of the trials, the absence of pilot outcome data using the specific THAPCA protocol, the feasibility of obtaining parental consent and initiating the therapy within the narrow therapeutic window in a critically ill pediatric population, the ability to obtain primary outcome data on patients with significant disability or in long-term care at 12 months, the agreement and cooperation of the various specialists to enroll patients and whether there was equipoise regarding the study interventions.
In response, the NHLBI agreed to fund an 18-month vanguard phase during which time the study was required to meet pre-specified milestones and demonstrate participant safety and study feasibility in order for NHLBI to consider financial support for the full trial. The goals of the THAPCA vanguard phase were to:
- Provide six months to complete administrative activities for study launch.
- Limit financial exposure by providing funds for 18 months, recruiting at half the number of proposed sites and basing future funding on achieving pre-specified milestones.
- Establish the feasibility of recruiting, consenting parents and initiating the study intervention within six hours in critically ill children being cared for by multiple subspecialists.
- Demonstrate the ability to obtain primary outcome data.
- Ensure that the trials could be conducted safely.
- Identify operational efficiencies with the potential to enhance study success.
Near the end of the enrollment period, an administrative review of the study was planned to evaluate feasibility, progress and safety, assess continued relevance of the scientific questions and determine the trial’s future.
This paper presents the lessons learned and challenges of implementing a vanguard phase in a complex trial in critically ill children and provides information to help investigators determine whether a vanguard phase might be an appropriate approach for other complex clinical trials.