Consequences of Directive 2001/20/EC for investigator-initiated trials in the paediatric population--a field report.

On 4 April 2001, the European Parliament and Council enacted Directive 2001/20/EC, which had to be implemented in the national law of the European Union member states by May 2004. Its aim was to improve the quality of clinical trials and to assure the safety and well-being of trial subjects. We recently initiated the first paediatric investigator-initiated trial (IIT) at the University Hospital of Cologne according to Directive 2001/20/EC. This field report demonstrates the consequences and implications of the directive for paediatric IITs. Based on our experience, we agree that Directive 2001/20/EC improves the quality of clinical trials and assures the safety and well-being of trial subjects. However, at the same time, performing an IIT according to the new requirements is nearly impossible for clinicians and academic researchers without cooperating with expensive specialised experts, such as project managers, statisticians, data managers, pharmacists and monitors. Therefore, it is absolutely mandatory that financial support for paediatric IITs be adapted and increased in order to be able to meet the new requirements and obligations. Regulation (EC) No 141/2000 on orphan medicinal products and the recently adopted regulation on medicinal products for paediatric use (Paediatric Regulation) are important steps in improving clinical research in children. However, both regulations mainly encourage clinical research carried out by the pharmaceutical industry, whereas paediatric IITs are not in the scope of this legislation. We need to develop new concepts for funding to ensure future paediatric IITs, for example through specific grants from the European Union or member states.

Successful plasma therapy for atypical hemolytic uremic syndrome caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15.

Quantitative or functional deficiency of complement factor H results in uncontrolled complement activation. This leads to thrombotic microangiopathy and finally causes renal failure (atypical hemolytic uremic syndrome [aHUS]). By regular analysis of factor H in patients with aHUS, the authors found a complete factor H deficiency in an infant in whom aHUS developed at 8 months of age. Factor H was quantified by enzyme-linked immunosorbent assay and further analyzed by Western blot using a factor H-specific antibody. Complement activation was determined by measuring total hemolytic activity of the classical (CH50) and alternative (APH50) pathways, C3 and C3d. The sequence of factor H gene was determined. Serial factor H measurements after fresh frozen plasma infusion allowed calculation of a factor H half-life. Factor H was absent in plasma (<1 mug/mL), and the complement system was highly activated (CH50, APH50, C3 decreased; C3d increased). Genetic analysis identified a novel homozygous factor H mutation (T2770A; Y899Stop) in CCP domain 15, most likely causing defective protein secretion. Time course measurements of factor H after plasma infusion established a factor H half-life of about 6 days. By repetitive plasma infusions (20 mL/kg over about 2 to 3 hours) the authors were able to interrupt the vicious circle of thrombotic microangiopathy in a factor H-deficient patient with aHUS. Based on the measured factor H half-life of about 6 days, regular plasma infusions in 2-week intervals were given, which prevented further aHUS episodes and stopped the decline of kidney function.