Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial

BACKGROUND: The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer. METHODS: In this open-label, randomised, phase 3 trial, we randomly assigned patients (1:1 ratio) with advanced, measurable, non-resectable colorectal cancer and WHO performance status 0-2 to receive either first-line treatment with bolus (400 mg/m(2)) and infusional (2400 mg/m(2)) fluorouracil plus leucovorin (400 mg/m(2)) (simplified LV5FU2 regimen), second-line LV5FU2 plus oxaliplatin (100 mg/m(2)) (FOLFOX6), and third-line LV5FU2 plus irinotecan (180 mg/m(2)) (FOLFIRI) or first-line FOLFOX6 and second-line FOLFIRI. Chemotherapy was administered every 2 weeks. Randomisation was done centrally using minimisation (minimisation factors were WHO performance status, previous adjuvant chemotherapy, number of disease sites, and centre). The primary endpoint was progression-free survival after two lines of treatment. Analyses were by intention-to-treat. This trial is registered at ClinicalTrials.gov, NCT00126256. FINDINGS: 205 patients were randomly assigned to the sequential group and 205 to the combination group. 161 (79%) patients in the sequential group and 161 (79%) in the combination group died during the study. Median progression-free survival after two lines was 10·5 months (95% CI 9·6-11·5) in the sequential group and 10·3 months (9·0-11·9) in the combination group (hazard ratio 0·95, 95% CI 0·77-1·16; p=0·61). All six deaths caused by toxic effects of treatment occurred in the combination group. During first-line chemotherapy, significantly fewer severe (grade 3-4) haematological adverse events (12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group; p<0·0001) and non-haematological adverse events (26 events vs 186 events; p<0·0001) occurred in the sequential group than in the combination group. INTERPRETATION: Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced, non-resectable colorectal cancer. FUNDING: Sanofi-Aventis France

Pharmaceutical research in paediatric populations and the new EU Paediatric Legislation: an industry perspective

A large proportion of medicines used in children are prescribed off-label, and children have often been denied access to new or innovative medications. Because such situation is unethical, the need to obtain paediatric information for medicines used in children seems nowadays a matter of consensus on a global basis. Based on this, it was clear in EU, like what has happened in the US, that there was a need for a legal obligation for Pharmaceutical Companies to perform studies. This new European Paediatric Regulation that entered into force in 2007 opens a new era of European drug regulatory history and will offer a major opportunity to improve children's health through advancements in research by providing a new framework for evaluating the efficacy and safety of medicines for children. But, paediatric development remains challenging and the hurdles of conducting research in paediatric population are numerous. The article presents the new European Paediatric Regulation, illustrates its rationale through paediatric psychopharmacology, and discusses some of its consequences on paediatric research from an industry perspective. Recommendations for further international collaboration are also suggested to make global paediatric development plans

Recent developments and strategies in pediatric pharmacology research in the USA

Research in pediatric pharmacology has undergone major changes in the last ten years, with an expansion in both publicly and privately funded activities. A number of pharmacokinetics studies and multi-site controlled efficacy trials have been conducted, so that treatment of children and adolescents can now be better informed and evidence-based. Regulatory financial incentives to industry in return for studies on drugs still covered by patent exclusivity have resulted in a substantial increase in pediatric research funded by pharmaceutical companies. In parallel, public funding has supported research on off-patent medications and other clinical important aspects of treatment, such as comparisons between active treatments, including non-pharmacological interventions. With greater interest by industry in pediatric research, the role of government funding agencies has been redefined to avoid duplication and ensure better integration of efforts and utilization of resources. The present review discusses some of the recent developments in pediatric pharmacology with focus on psychiatric medications

Codice ReNEUAL del procedimento amministrativo dell’Unione Europea

Lo scopo del progetto di Codice ReNEUAL del procedimento amministrativo dell\u2019Unione Europea avviato dalla Research Network on EU Administrative Law (ReNEUAL) consiste nell\u2019individuare i percorsi pi\uf9 adatti per tradurre i valori costituzionali dell\u2019Unione Europea in norme sul procedimento amministrativo aventi come oggetto l\u2019attuazione non legislativa del diritto dell\u2019Unione e delle politiche europee. Norme adeguatamente strutturate per l\u2019attuazione del diritto dell\u2019Unione e delle politiche europee potrebbero migliorare la qualit\ue0 dell\u2019ordinamento giuridico dell\u2019Unione europea, in quanto esse hanno il potenziale per incrementare l\u2019osservanza dei principi generali del diritto dell\u2019Unione Europea, contribuire a semplificare l\u2019ordinamento giuridico, rafforzare la certezza del diritto e colmare i vuoti presenti nell\u2019ordinamento giuridico. Il Codice modello ReNEUAL si articola in sei Libri. Lo scopo di tali libri consiste nel rinforzare i principi generali del diritto dell\u2019Unione Europea e nell\u2019individuare, alla luce di una ricerca comparata, le migliori prassi delineate in diverse politiche specifiche dell\u2019Unione Europea.(1) The project on ReNEUAL Model Rules on EU administrative procedure undertaken by the Research Network on EU Administrative Law (ReNEUAL) aims to determine how constitutional values of the Union can be best translated into rules on administrative procedure covering non-legislative implementation of EU law and policies. Well-designed rules for implementation of EU law and policies could improve the quality of the EU\u2019s legal system. They have the potential to add to the compliance with general principles of EU law, to help simplify the legal system, enhance legal certainty and fill gaps in the legal system. The ReNEUAL Model Rules are organised in six \u2018books\u2019. These books are designed to reinforce general principles of EU law and identify - on the basis of comparative research - best practices in different specific policies of the EU