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.