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Aims: In the EU, development of new medicines for children should follow a prospectively agreed paediatric investigation plan (PIP). Finding the right dose for children is crucial but challenging due to the variability of pharmacokinetics across age groups and the limited sample sizes available. We examined strategies adopted in PIPs to support paediatric dosing recommendations to identify common assumptions underlying dose investigations and the attempts planned to verify them in children., Methods: We extracted data from 73 PIP opinions recently adopted by the Paediatric Committee of the European Medicines Agency. These opinions represented 79 medicinal development programmes and comprised a total of 97 dose investigation studies. We identified the design of these dose investigation studies, recorded the analyses planned and determined the criteria used to define target doses., Results: Most dose investigation studies are clinical trials (83 of 97) that evaluate a single dosing rule. Sample sizes used to investigate dose are highly variable across programmes, with smaller numbers used in younger children (< 2 years). Many studies (40 of 97) do not pre-specify a target dose criterion. Of those that do, most (33 of 57 studies) guide decisions using pharmacokinetic data alone., Conclusions: Common assumptions underlying dose investigation strategies include dose proportionality and similar exposure-response relationships in adults and children. Few development programmes pre-specify steps to verify assumptions in children. There is scope for the use of Bayesian methods as a framework for synthesizing existing information to quantify prior uncertainty about assumptions. This process can inform the design of optimal drug development strategies., (© 2014 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

Ethical and practical constraints encourage the optimal use of resources in pediatric drug development. Modeling and simulation has emerged as a promising methodology acknowledged by industry, academia, and regulators. We previously proposed a paradigm in pediatric drug development, whereby modeling and simulation is used as a decision tool, for study optimization and/or as a data analysis tool. Three and a half years since the Paediatric Regulation came into force in 2007, the European Medicines Agency has gained substantial experience in the use of modeling and simulation in pediatric drug development. In this review, we present examples on how the proposed paradigm applies in real case scenarios of planned pharmaceutical developments. We also report the results of a pediatric database search to further 'validate' the paradigm. There were 47 of 210 positive pediatric investigation plan (PIP) opinions that made reference to modeling and simulation (data included all positive opinions issued up to January 2010). This reflects a major shift in regulatory thinking. The ratio of PIPs with modeling and simulation rose to two in five based on the summary reports. Population pharmacokinetic (POP-PK) and pharmacodynamics (POP-PD) and physiologically based pharmacokinetic models are widely used by industry and endorsed or even imposed by regulators as a way to circumvent some difficulties in developing medicinal products in children. The knowledge of the effects of age and size on PK is improving, and models are widely employed to make optimal use of this knowledge but less is known about the effects of size and maturation on PD, disease progression, and safety. Extrapolation of efficacy from different age groups is often used in pediatric medicinal development as another means to alleviate the burden of clinical trials in children, and this can be aided by modeling and simulation to supplement clinical data. The regulatory assessment is finally judged on clinical grounds such as feasibility, ethical issues, prioritization of studies, and unmet medical need. The regulators are eager to expand the use of modeling and simulation to elucidate safety issues, to evaluate the effects of disease (e.g., renal or hepatic dysfunction), and to qualify mechanistic models that could help shift the current medicinal development paradigm., (© 2011 Blackwell Publishing Ltd.)

Background and Methods: At the end of 2003, the Competence Network Paediatric Oncology and Haematology conducted a survey of paediatric oncology centres in Germany as one of its measures to support and advance the collaboration of paediatric oncology centres and trials in science and health care. There was a lack of key figures to describe their combined position in the health care system. The survey aimed to quantify existing structures in terms of personnel, facilities, and patients as well as to collect preliminary information on patterns of care and on quality assurance. Starting with the largest patient numbers, 53 German centres were included, which cared for at least 10 patients under the age of 15 years with a newly diagnosed malignant disease per year., Main Results: 49 (92%) centres contributed to the survey. 40 centres cared for a total of 1712 patients under the age of 15 years with a first occurrence of a malignant disease, which corresponds to 83% of all such patients registered in the German Childhood Cancer Registry in 2003. The total number of patients cared for in these centers, which also includes those with a relapse and the above 15-year olds, exceeds the Registry numbers by about 50%. The survey's outcome on staffing revealed about two work positions per bed (in-patient or day-clinic). A significant part of this personnel is financed by third-party funds. On average, the centres responding to the survey were equipped with 7 physician, 21 nursing and 4,4 psychologist, social worker, medical documentarist, and secretariat posts to care for a mean of 54 patients or 18 in-patient beds. Including those working positions financed by third-party funds, the majority of centres scored staffing as good or excellent. Yet, one out of ten centres scored the staffing of one or more occupational groups as poor., Conclusions: The survey provided for the first time a national assessment of the variable levels of staffing and facilities in the most relevant German paediatric oncology centres. The data indicate that the relationship between several key figures such as the Registry patient subset's numbers and in-patient bed numbers, for example, is weak, whereas physician post numbers, for example, correlate reasonably well with actual patient numbers. Further data include the variety of special health care offered and preliminary provisions for quality assurance per centre. According to a comparison with a seminal publication on needs in German paediatric oncology health care published in 1991 and with a needs survey of the UK National Institute for Health and Clinical Excellence (NICE), there seems to be an insufficient response to the needs, which is undermined by the centres survey responses. In view of the DRG reimbursement system being introduced throughout German health care, future surveys should also focus on key figures related to the DRG system such as case numbers, but such data should be merged with patient data in order to maintain a perspective on the course of health care provision to children and young adults with cancer.

The German 'Competence Network Paediatric Oncology and Haematology' aims at improving the structure of paediatric oncology and haematology as a whole, focussing in particular on the quality of clinical trials and study co-ordinating centres. This comprises the following measures: (1) Employment of research and trial assistants in order to improve the quality of documentation and study management in the participating hospitals. (2) Development of an internet portal to provide medical information for non-professionals, for patients and their families as well as for health professionals. (3) The project group 'Central Trial Support' supports study centres during the process of writing and examining new treatment protocols so that they are in compliance with the Good Clinical Practice criteria, formal criteria, legal requirements and statutory provisions. This group currently produces a structural standardisation of study protocols and case record forms in order to improve their usability. The 'Competence Network Malignant Lymphomas' is a project with similar aims and will be outlined for comparison.

The project group "Central Trial Support" of the German Competence Network Pediatric Oncology and Haematology supports the members of the Society of Pediatric Oncology and Haematology in their effort to cope with the growing statutory, ethical and administrative requirements for therapy optimization studies (investigator-initiated, non-profit clinical trials). By these quality improvement measures the studies will become more revisable and reliable, but at the same time their processing will become more and more complex. The basic instrument of the project group "Central Trial Support" will be the so-called "Quality House" which has been built up in order to improve the performance of the associated study centres and to help put a systematic quality management system into practice. The "Quality House Pediatric Oncology" comprises detailed descriptions of the activities of all trial center co-workers. Its process map details all operational sequences which constitute an efficiently performing trial center. The so-called value adding processes are explained step by step, and the associated specific tasks are assigned to each respective co-worker. At each process step, the person in charge will have explanatory descriptions at her/his disposal and - if necessary - further problem solving means as well as references to possible optimization measures (e. g. Standard Operating Procedures and other documents). The German Competence Network Pediatric Oncology and Haematology will be implementing this electronic quality management system in trial centers which will convince both sponsors and authorities of the compliance with requirements and standards.

For more than 30 years Paediatric Oncology has striven to achieve an optimum of care for children with cancer everywhere. The consistency of diagnostic procedures and treatment within successive therapy studies has yielded high cure rates. Meanwhile the focus has moved to placing the quality control of diagnostics and treatment into the hands of experts in the field, accommodating new requirements of the health care system. We report on the already realised and the future concepts and methods employed in improving the quality in institutions and studies with the support of the German Competence Network in Paediatric Oncology and Haematology (Kompetenznetz Padiatrische Onkologie und Hamatologie, KPOH). The issue of per-patient flat rate funding is raised, and structural requirements to be fulfilled by Centers of Paediatric Oncology are presented and discussed.

Objective: Chemotherapy planning in pediatric oncology is complex and time-consuming. The correctness of the calculation according to state-of-the-art research is crucial for curing the child. Computer-assistance can be of great value. The objective of our research was to work out a meta-model of chemotherapy planning based on the Unified Modeling Language (UML). The meta-model is used for the development of an application system which serves as a knowledge-acquisition tool for chemotherapy protocols in pediatric oncology as well as for providing protocol-based care., Methods: We applied evolutionary prototyping, software reengineering techniques and grounded theory, a qualitative method in social research. We repeated the following steps several times over the years: Based on a requirements analysis (i) a meta-model was developed or adapted, respectively (ii). The meta-model served as a basis for implementing evolutionary prototypes (iii). Further requirements were identified (i) from clinical use of the systems., Results: We developed a comprehensive UML-based meta-model for chemotherapy planning in pediatric oncology (chemoMM). We implemented it and introduced evolutionary prototypes (CATIPO and DOSPO) in several medical centers. Systematic validation of the prototypes enabled us to derive a final meta-model which covers the requirements that have turned out to be necessary in clinical routine., Conclusions: We have developed an application system that fits well into clinical routine of pediatric oncology in Germany. Validation results have shown that the implementation of the meta-model chemoMM can adequately support the knowledge acquisition process for protocol-based care.

The competence network paediatric oncology and haematology aims at improving the structure of paediatric oncology and haematology as a whole focussing in particular on the quality of clinical trials and study centres. This implicates the following measures: (1) Employment of research and trial assistants in order to improve the quality of documentation and study management in the participating hospitals. (2) Building up of an Internet portal to provide medical information for non-professionals, for patients and their families as well as for health professionals. (3) The project "Study Assistance" supports study centers during the process of writing and examining new treatment protocols so that they are in compliance with the Good Clinical Practice criteria, formal criteria and statutory provisions. It presently works on a structural standardisation of study protocols and case record forms in order to improve their usability. In addition, the working group "Quality Assurance in GPOH Study Centres" is engaged in developing a quality management system for study centers.