Mentoring in Pediatric Cardiovascular Pharmacology and Early Phase Trials

Cardiovascular (CV) therapeutics remain dangerously understudied in children: of 1055 FDA pediatric label changes under BPCA and PREA since 1998, only 29 were in CV drugs, and >90% of the sickest children with CV disease in intensive care units are exposed to ≥1 off-label drug, a practice known to worsen outcomes.

Modern approaches to pediatric drug labeling are based on pharmacometric models to evaluate drug exposure response relationships, and when appropriate correlate them with adult findings. A lack of pediatric CV patient- oriented scientists trained in these methods is the primary obstacle to more widespread labeling of CV drugs.

With my unique background in pediatric cardiology and critical care, biostatistics, clinical pharmacology, and innovative early-phase clinical trial and real-world data utilization, I am exceptionally well positioned to close this training gap in junior CV patient-oriented scientists. Now in my 10th year on faculty at Duke and the Duke

Clinical Research Institute (DCRI), I built an NIH, FDA, and foundation funded research portfolio of early-phase pharmacokinetic (PK)/ pharmacodynamic trials, regulatory compliant pharmacometric modeling and simulation, and innovative real-world-data utilization to study pediatric CV drug development. I systematically leveraged

my portfolio to create opportunities for training and mentoring for 23 trainees to date. With the support of this K24, I will expand my mentorship and training program to a larger number of more diverse trainees, and obtained formal skills in mentorship, novel modeling techniques, and innovative real-world-data applications. I

have developed and secured funding for an innovative, point-of-care, electronic health record data enabled multi-drug platform PK/PD trial, OPTIC, designed specifically for training and mentorship. In this platform trial, each trainee owns a single CV drug studied within a multi-drug protocol which I oversee, and will receive

hands-on training from protocol writing through enrolling of subjects and data analysis for their drug. Coupled with an expectation for formal didactic coursework towards a master’s or PhD degree in quantitative sciences at Duke or the University of North Carolina (UNC), my trainees will receive rigorous training to prepare them as

independently funded patient-oriented investigators focused on pediatric CV clinical pharmacology. In addition to my own funding, the proposed training program is supported by an exceptional research environment at DCRI including the NICHD funded Pediatric Trials Network focused on pediatric drug development, and my

leadership roles as Director of the DCRI Pharmacometrics Center, and Program Director of a joint Duke-UNC T32 training program in clinical pharmacology. DCRI’s unique pipeline of NIH funded clinical research training programs, ranging from R38 summer programs for undergraduate students to early-career faculty K12 awards

are ideal to recruit trainees. While rigorous and demanding, the feasibility of my proposed training program is supported by my success with funding and career development of current trainees including: 62 first-author publications with me, multiple early-career and NIH awards; >80% of graduates in academic positions.