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Background and objective: During the drug development process, phase I trials are the first occasion to study the pharmacokinetics of a drug. They are performed in healthy subjects, or in patients in oncology, and are designed to determine a safe and acceptable dose for the later phases of clinical trials. We performed a bibliographic survey to investigate the way pharmacokinetics are described and reported in phase I clinical trials. Methods: We performed a MEDLINE search to retrieve the list of papers published between 2005 and 2006 and reporting phase I clinical trials with a pharmacokinetic study. We used a spreadsheet to record general information concerning the study and specific information regarding the pharmacokinetics, such as the sampling times, number of subjects and method of analysis. Results: The search yielded 349 papers, of which 37 were excluded for various reasons. Nearly all of the papers in our review concerned cancer studies, although this was not a requirement in the search. Consistent with the selection process, 84% papers explicitly stated pharmacokinetics as an objective of the study. The methods section usually included a description of the pharmacokinetics (88%), but 10% of the papers provided no information concerning the methods used for the pharmacokinetics and in 2%the description was only partial. The analytical method was usually basic, with non-compartmental or purely descriptive methods. Observed concentrations and areas under the concentration-time curves were the pharmacokinetic variables most often reported. The results of the pharmacokinetic study were frequently reported in a separate paragraph of the results section, and only 22% of the studies related the pharmacokinetic findings to other results from the study, such as toxicity or efficacy. In addition, important information such as the number of subjects included in the pharmacokinetic study or the pharmacokinetic sampling scheme was sometimes not reported explicitly. Conclusion: Concerns about the decreasing cost-effectiveness of the drug development process prompted the regulatory authorities to recently recommend better integration of all available information -- including, in particular, pharmacokinetics -- in this process. In our review, we found that this information was often either missing or incomplete, which hinders that objective. We suggest several improvements in the design and the reporting of the methods and results of these studies, to ensure that all relevant information has been included. Pharmacokinetic findings should also be integrated into the broader perspective of drug development, through the study of their relationship with toxicity and/or efficacy, even in the early phase I stages. [ABSTRACT FROM AUTHOR]

The number of trials conducted and the number of patients per trial are typically small in paediatric clinical studies. This is due to ethical constraints and the complexity of the medical process for treating children. While incorporating prior knowledge from adults may be extremely valuable, this must be done carefully. In this paper, we propose a unified method for designing and analysing dose-finding trials in paediatrics, while bridging information from adults. The dose-range is calculated under three extrapolation options, linear, allometry and maturation adjustment, using adult pharmacokinetic data. To do this, it is assumed that target exposures are the same in both populations. The working model and prior distribution parameters of the dose-toxicity and dose-efficacy relationships are obtained using early-phase adult toxicity and efficacy data at several dose levels. Priors are integrated into the dose-finding process through Bayesian model selection or adaptive priors. This calibrates the model to adjust for misspecification, if the adult and pediatric data are very different. We performed a simulation study which indicates that incorporating prior adult information in this way may improve dose selection in children. [ABSTRACT FROM AUTHOR]

Where there are a limited number of patients, such as in a rare disease, clinical trials in these small populations present several challenges, including statistical issues. This led to an EU FP7 call for proposals in 2013. One of the three projects funded was the Innovative Methodology for Small Populations Research (InSPiRe) project. This paper summarizes the main results of the project, which was completed in 2017.The InSPiRe project has led to development of novel statistical methodology for clinical trials in small populations in four areas. We have explored new decision-making methods for small population clinical trials using a Bayesian decision-theoretic framework to compare costs with potential benefits, developed approaches for targeted treatment trials, enabling simultaneous identification of subgroups and confirmation of treatment effect for these patients, worked on early phase clinical trial design and on extrapolation from adult to pediatric studies, developing methods to enable use of pharmacokinetics and pharmacodynamics data, and also developed improved robust meta-analysis methods for a small number of trials to support the planning, analysis and interpretation of a trial as well as enabling extrapolation between patient groups. In addition to scientific publications, we have contributed to regulatory guidance and produced free software in order to facilitate implementation of the novel methods. [ABSTRACT FROM AUTHOR]