Collaborations / Networks

Less than half of all authorised medicines commonly used in children have been properly tested in this group, and running clinical trials involving children is hard. The conect4children (c4c) project aims to create a sustainable, integrated pan-European collaborative paediatric network that will speed up and facilitate the running of high quality clinical trials in children while ensuring that the voices of young patients and their families are heard. It will build the capacity for conducting multinational paediatric clinical trials for all disease areas and all phases of the clinical drug development process. One focus of the project is to promote innovative trial designs that will support drug development for rare paediatric diseases and areas of high medical need. The project will also set up an education and training platform for future leaders in paediatric drug development. Ultimately, the paediatric clinical trials network will contribute to the development of better medicines for babies, children and young people.

The GermanNetPaeT was founded in 2018 as part of the Innovative Medicines Initiative 2 (IMI 2) conect4children (c4c). Aim of the GermanNetPaeT is to improve pharmacotherapy in paediatric patients regarding safety and efficacy by making clinical trials in children and adolescents more effective. Ultimate goal is to provide highly potent medicines for children and adolescents. Major prerequisite is an improved liaison between pharmaceutical industry and paediatric clinical study centres comprising all issues to conduct clinical trials. Particular interest is given on Harmonisation of Documents & Procedures, Ethics & Regulations, Pharmacovigilance, Training & Education, Applied Biometry and Patient & Parent Involvement. One key feature of the GermanNetPaeT is the Single Point of Contact (SPoC) located at the head office at the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart. Currently more than 20 paediatric clinical study centres at hospitals for paediatrics and adolescent medicine and child and adolescent psychiatry are part of the GermanNetPaeT. The Network of Coordinating Centers for Clinical Studies (KKSN) strongly supports the GermanNetPaeT initiative. On behalf of the German Society of Pediatrics and Adolescent Medicine (DGKJ) all expert associations and working groups represented by the convent for collaboration of experts are affiliated. This guarantees the integration of experts for all paediatric subspecialities. Patient and parent representatives are also actively involved.

German Hub Leader: Matthias Schwab, MD - Head of the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

Pharmacogenomics (PGx) is the study of genetic variability affecting an individual’s response to a drug. Clinical application of pharmacogenomics knowledge will result in less ‘trial and error’ prescribing and more efficacious, safer and cost-effective drug therapy. However, despite the major advances in PGx and several commercially available PGx tests, its application in routine patient care remains very limited.
The U-PGx consortium will address major challenges and obstacles for implementation of PGx testing in patient care, taking into account the diversity of healthcare systems and citizens across Europe. Specifically, U-PGx will investigate if the emerging approach of pre-emptive genotyping of an entire panel of important PGx markers is cost-effective and results in a better outcome for patients. With the pre-emptive PGx testing approach data on multiple important pharmacogenes are collected prospectively and embedded into the patients’ electronic record. Typically, it alerts prescribers and pharmacists through electronic clinical decision support systems when a drug is ordered or dispensed for a patient with an at-risk genotype. The new model of personalised medicine through pre-emptive PGx-testing will be conducted at a large scale in seven existing European health care environments including The Netherlands, Spain, UK, Italy, Austria, Greece, and Slovenia.

Vice-Chairman of the Consortium, Leader Component III:
Matthias Schwab, MD - Head of the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

Breast cancer is the most frequent malignancy in women with approximately 1.7 Mio new cases per year worldwide. More than ¾ of these tumors overexpress the estrogen receptor and are therefore susceptible to an anti-hormone therapy. The standard-of-care in endocrine treatment is the blockade of estrogen signaling via long-term estrogen deprivation. Tumors are therefore treated with long-term antihormone therapy for at least 5 years. Tamoxifen, a selective estrogen receptor modulator (SERM) blocks 17ß-estradiol binding to stop tumor growth, and aromatase inhibitors (AI) block the aromatase enzyme to prevent conversion of androgens to estrogens. Despite their effectiveness one third of the patients develop recurrences leading to disease progression and death. With regards to Tamoxifen, treatment failure is attributed at least in part to a lack of bioactivation towards its active metabolite endoxifen which is mainly mediated by the polymorphic CYP2D6 enzyme.  Distinct genetically determined variants in the CYP2D6 gene are responsible for inter-individual differences in CYP2D6 enzyme activities throughout the general population. These CYP2D6 phenotypes are grouped into ultra-rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. EM patients have high levels of endoxifen and are likely to benefit from tamoxifen treatment whereas PM patients have low endoxifen levels and a significant risk to relapse. CYP2D6 polymorphism and plasma endoxifen levels have been discussed as tamoxifen outcome predictors and the supplementation of standard tamoxifen (20 mg) with endoxifen is a current clinical trial concept, TAMENDOX, to test whether suboptimal endoxifen levels (< 15 nM) in PM and IM patients can be elevated to clinically meaningful endoxifen concentrations (>32 nm). The purpose of TAMENDOX is to demonstrate feasibility as a prerequisite to pursue this new drug concept of combining the parent drug tamoxifen with its active metabolite endoxifen towards the improvement of tamoxifen outcome which is relevant to millions of women worldwide.

Estimated start of the trial: autumn 2018

Principal Investigator: Matthias Schwab, MD - Head of the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

University of Hohenheim in cooperation with the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and the Robert Bosch Hospital

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen