Pharmacologic studies in vulnerable populations: Using the pediatric experience

Zimmerman, Kanecia O.; González, Daniel; Swamy, Geeta K.; Cohen‐Wolkowiez, Michael

doi:10.1053/j.semperi.2015.08.007

Cited by 22 publications

(22 citation statements)

References 24 publications

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“…In addition to these advances pediatric clinical trials are incentivized through legislative requirements enacted by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and regulatory bodies in Asia. [1][2][3] In the United States, for example, the Pediatric Research Equity Act permits the FDA to require that pediatric studies be conducted for drugs that are likely to be used in children or from which children are likely to receive significant benefit, whereas the Best Pharmaceuticals for Children Act offers extended patent protection, exclusivity, and governmental authority to request studies of off-patent drugs. 4 Despite advances, 42% of recent pediatric trials failed in achieving labeling indications, highlighting the unique difficulty of establishing drug efficacy and safety in children.…”

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confidence: 99%

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

Balevic

Cohen‐Wolkowiez

2018

The Journal of Clinical Pharma

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Almost half of recent pediatric trials failed to achieve labeling indications, due in large part to inadequate study design. Therefore, innovative study methods are crucial to optimize trial design while also reducing the potential harms inherent with drug investigation. Several methods exist to optimize the amount of pharmacokinetic (PK) data collected from the smallest possible volume and with the fewest number of procedures, including the use of opportunistic and sparse sampling, alternative and non-invasive matrices, and micro-volume assays. In addition, large research networks using master protocols promote collaboration, reduce regulatory burden, and increase trial efficiency for both early- and late-phase trials. Large pragmatic trials that leverage electronic health records can capitalize on central management strategies to reduce costs, enroll patients with rare diseases on a large scale, and augment study generalizability. Further, trial efficiency and safety can be optimized through Bayesian adaptive techniques that permit planned protocol changes based on analyses of prior and accumulated data. In addition to these trial design features, advances in modeling and simulation have paved the way for systems-based and physiologically-based models that individualize pediatric dosing recommendations and support drug approval. Lastly, given the low prevalence of many pediatric diseases, collecting de-identified genetic and clinical data on a large scale is a potentially transformative way to augment clinical pharmacology research in children.

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Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

Balevic

Cohen‐Wolkowiez

2018

The Journal of Clinical Pharma

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“…6,76 While reasons for the relative lack of studies are likely multifactorial, low consent rates, cost, and current study designs that interfere with the complex and high stakes clinical care delivered in the post-operative setting are likely key drivers. 8,77 Parental, as well as provider, stress, and anxiety, coupled with children being at significant medical and surgical risk while undergoing invasive procedures, is also likely to reduce consent rates. 78,79 Even for those patients who do get enrolled in a trial, study designs with extensive protocol-specific procedures may result in a large number of protocol deviations, study drop-outs, and decreased participation.…”

Section: Current Knowledge Gapsmentioning

confidence: 99%

An evidence-based review of the use of vasoactive and inotropic medications in post-operative paediatric patients after cardiac surgery with cardiopulmonary bypass from 2000 to 2020

et al. 2020

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Background: Infants with moderate-to-severe CHD frequently undergo cardiopulmonary bypass surgery in childhood. Morbidity and mortality are highest in those who develop post-operative low cardiac output syndrome. Vasoactive and inotropic medications are mainstays of treatment for these children, despite limited evidence supporting their use. Methods: To help inform clinical practice, as well as the conduct of future trials, we performed a systematic review of existing literature on inotropes and vasoactives in children after cardiac surgery using the PubMed and EMBASE databases. We included studies from 2000 to 2020, and the patient population was defined as birth – 18 years of age. Two reviewers independently reviewed studies to determine final eligibility. Results: The final analysis included 37 papers. Collectively, selected studies reported on 12 different vasoactive and inotropic medications in 2856 children. Overall evidence supporting the use of these drugs in children after cardiopulmonary bypass was limited. The majority of studies were small with 30/37 (81%) enrolling less than 100 patients, 29/37 (78%) were not randomised, and safety and efficacy endpoints differed widely, limiting the ability to combine data for meta-analyses. Conclusion: Vasoactive and inotropic support remain critical parts of post-operative care for children after cardiopulmonary bypass surgery. There is a paucity of data for the selection and dosing of vasoactives and inotropes for these patients. Despite the knowledge gaps that remain, numerous recent innovations create opportunities to rethink the conduct of clinical trials in this high-risk population.

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“…Beyond studying children of all ages, the problem of the correct dose for obese or underweight children is beginning to get attention. Perhaps more importantly, the advances that are being made to support drug development work in children, including in fragile newborns, can be extended to the study of other vulnerable populations such as pregnant and lactating women . The goal of perfect pediatric posology may indeed be at hand.…”

Section: Next Steps and Remaining Questionsmentioning

confidence: 99%

The Path to Perfect Pediatric Posology — Drug Development in Pediatrics

Korth‐Bradley

2018

The Journal of Clinical Pharma

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Reluctance to enroll pediatric subjects in clinical trials has left gaps in information about dosing, safety, and efficacy of medications. Pharmacotherapeutic information for pediatric patients may be available for only a small range of ages and may be deficient, as children respond differently as they grow and mature from prematurity to adolescence. Current regulations, however, require early planning for the participation of children in drug development, as pediatric plans must be submitted at the end of phase 1 (European Union) or the end of phase 2 (United States). These plans are extensive, outlining planned studies, subjects to be enrolled, dose and dosage form justification, planned observations, and statistical analysis as well as planned modeling, simulation, and extrapolation analyses. The extent to which efficacy information in adults can be extrapolated to children depends on how similar the disease is in adults and each of the 5 pediatric age groups. Extrapolation may not be possible for conditions that do not occur in adults, requiring a complete development plan in adults, or extrapolation may be complete because of similar pathology and response to treatment. Pharmacokinetic and safety information cannot be extrapolated and must be collected in children of all ages, unless a waiver is granted. Physiologically based pharmacokinetic modeling, optimal design, population pharmacokinetics, and scavenged samples are all examples of new methodologies being used to study pediatric therapeutics. Clinicaltrials.gov and EU Clinical Trials registry are good sources of results of pediatric trials, although sponsors are also working toward prompt publication of study results in peer‐reviewed journals.

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Pharmacologic studies in vulnerable populations: Using the pediatric experience

Cited by 22 publications

References 24 publications

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

An evidence-based review of the use of vasoactive and inotropic medications in post-operative paediatric patients after cardiac surgery with cardiopulmonary bypass from 2000 to 2020

The Path to Perfect Pediatric Posology — Drug Development in Pediatrics

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