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

Abstract

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.

Framework conditions facilitating paediatric clinical research

“…The regulation should also have included obligations for applicants regarding off-label drugs (i.e., drugs administered for a different purpose from that studied and reviewed for licensing) which are very commonly used in ordinary practice. Actually, clinical research on these products is rather complicated and the profit margin being low, pharmaceutical companies generally do not make off-label drugs available for children research [ 5 ].…”

“…Clinical trial monitoring according to a risk-based approach would be more appropriate for off-patent products. It would entail a substantial reduction of workload and cost, particularly for academic institutions that run low-risk studies using marketed drugs [ 5 , 34 ]. To define the legal risk of a clinical trial, insurance companies have a more quantitative and simplified approach of the risk/benefit assessment than scientists.…”

Academic pediatric clinical research: factors associated with study implementation duration

“…Osuntokun described this increasing regulatory burden over time, and discussed the difficulty for academic structures to apply the pediatrics regulations [ 5 ]. Indeed, these regulations are specifically targeted at pharmaceutical companies, and slow down academic research [ 24 , 38 ]. The upcoming European Clinical Trial Regulation should be a major determinant regarding this issue, particularly via the risk-proportionate approach.…”

“…Academic stakeholders must then grapple with the complexity of pediatrics regulations, which are actually targeted at the pharmaceutical industries. They then face the methodological, ethical, and technical requirements of pediatric clinical trials, often with limited financial resources [ 5 , 38 ]. The upcoming European Clinical Trial Regulation should be a major determinant regarding this issue, particularly via the risk-proportionate approach.…”

“…However, previous studies identified the heavy regulatory burden [ 5 , 25 – 28 ], the pharmaceutical issues and difficulties in establishing contracts with pharmaceutical companies [ 25 , 26 , 29 – 32 ], the inadequate training of investigators, difficulty functioning as both clinician and investigator [ 5 , 25 , 27 , 33 – 37 ], as well as suboptimal communication across disciplines involved [ 25 ], as the main obstacles in conducting academic pediatric studies. Further obstacles relate to the complexity of the 2001 European directive and variability in its interpretation across European Union countries which have resulted in further delays in conducting trials, and has contributed to the loss of European competitiveness in academic research over the past decade [ 24 , 38 ]. Delays affect the competitiveness and attractiveness of European clinical research, and may also be deleterious for the patients, which dissuades some medical doctors from participation in clinical trials [ 5 , 25 , 26 , 33 ].…”