Extrapolation in the development of paediatric medicines: examples from approvals for biological treatments for paediatric chronic immune-mediated inflammatory diseases.

The European Union (EU) Paediatric Regulation requires that all new medicinal products applying for a marketing authorisation (MA) in the EU provide a paediatric investigation plan (PIP) covering a clinical and non-clinical trial programme relating to the use in the paediatric population, unless a waiver applies. Conducting trials in children is challenging on many levels, including ethical and practical issues, which may affect the availability of the clinical evidence. In scientifically justified cases, extrapolation of data from other populations can be an option to gather evidence supporting the benefit-risk assessment of the medicinal product for paediatric use. The European Medicines Agency (EMA) is working on providing a framework for extrapolation that is scientifically valid, reliable and adequate to support MA of medicines for children. It is expected that the extrapolation framework together with therapeutic area guidelines and individual case studies will support future PIPs. Extrapolation has already been employed in several paediatric development programmes including biological treatment for immune-mediated diseases. This article reviews extrapolation strategies from MA applications for products for the treatment of juvenile idiopathic arthritis, paediatric psoriasis and paediatric inflammatory bowel disease. It also provides a summary of extrapolation advice expressed in relevant EMA guidelines and initiatives supporting the use of alternative approaches in paediatric medicine development.

Three years of paediatric regulation in the European Union.

PURPOSE: To investigate whether the Paediatric Regulation has already succeeded in addressing the needs of the paediatric population both quantitatively with respect to paediatric development plans and trials, and qualitatively with respect to the content of the plans. The Paediatric Regulation No 1901/2006 entered into force in Europe on 26 January 2007, with the aim to improve the development of medicinal products, to address the lack of age-appropriate formulations and to provide information on efficacy, safety and dosing for the paediatric population. The Regulation requires applications for marketing authorisations to be accompanied by either a product-specific waiver or a paediatric investigation plan, to be agreed by the Paediatric Committee (PDCO) of the European Medicines Agency (EMA). METHODS: A retrospective analysis of the applications for Paediatric Investigation Plans (PIPs) and Waivers submitted to the EMA, from 2007 until end of 2009, was performed. The content of scientific opinions adopted by the Paediatric Committee was compared to the proposals submitted by industry, and the paediatric clinical trials registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database were examined. RESULTS: An increasing paediatric medicine development can be expected following the adoption of this legal framework. The highest number of PIPs was in the fields of endocrinology (13.4%), oncology (11%) and infectious (10.8%) and cardiovascular diseases (7.1%), but most therapeutic areas now benefit from paediatric development. A large number of PIPs include measures for the development of age-appropriate formulations (23%), and most include studies on dosing, efficacy and safety to cover the respective paediatric subsets, including the mostly neglected neonates (26%). In many proposals (38%), however, the PDCO had to request major modifications to the proposed PIPs to ensure that the results will meet the needs, in particular by requesting better methodology. The proportion of paediatric trials as a percentage of all clinical trials has moderately increased (from 8.2 to 9.4% of all trials), and this may reflect the fact that paediatric trials are generally deferred (82%) until after adult development. CONCLUSIONS: This is the first analysis of the general impact of the Paediatric Regulation on the development of medicinal products in Europe. Three years after the implementation of the Paediatric Regulation, we were able to identify that the PIPs address the main gaps in knowledge on paediatric medicines. The key objective of the Paediatric Regulation, namely, the availability of medicines with age-appropriate information, is going to be achieved. It is clear also that modifications of the initial proposals as requested by the PDCO are necessary to ensure the quality of paediatric developments. The impact on the number of clinical trials performed remains modest at this point in time, and it will be of high interest to monitor this performance indicator, which will also inform us whether paediatric medicine research takes place in Europe or elsewhere.

High frequency of corticosteroid and immunosuppressive therapy in patients with systemic sclerosis despite limited evidence for efficacy.

INTRODUCTION: In systemic sclerosis (SSc) little evidence for the effectiveness of anti-inflammatory and immunosuppressive therapy exists. The objective of this study was to determine the extent to which SSc patients are treated with corticosteroids and immunosuppressive agents. METHODS: Data on duration and dosage of corticosteroids and on the type of immunosuppressive agent were analyzed from 1,729 patients who were registered in the German Network for Systemic Scleroderma (DNSS). RESULTS: A total 41.3% of all registered SSc patients was treated with corticosteroids. Corticosteroid use was reported in 49.1% of patients with diffuse cutaneous SSc and 31.3% of patients with limited cutaneous SSc (P < 0.0001). Among patients with overlap disease characteristics, 63.5% received corticosteroids (P < 0.0001 vs. limited cutaneous SSc). A total 16.1% of the patients received corticosteroids with a daily dose >or= 15 mg prednisone equivalent. Immunosuppressive therapy was prescribed in 35.8% of patients. Again, among those patients with overlap symptoms, a much higher proportion (64.1%) was treated with immunosuppressive agents, compared with 46.4% of those with diffuse cutaneous SSc sclerosis and 22.2% of those with limited cutaneous SSc (P < 0.0001). The most commonly prescribed drugs were methotrexate (30.5%), cyclophosphamide (22.2%), azathioprine (21.8%) and (hydroxy)chloroquine (7.2%). The use of these compounds varied significantly between medical subspecialties. CONCLUSIONS: Despite limited evidence for the effectiveness of corticosteroids and immunosuppressive agents in SSc, these potentially harmful drugs are frequently prescribed to patients with all forms of SSc. Therefore, this study indicates the need to develop and communicate adequate treatment recommendations.