1. Overcoming challenges in pediatric oncology product development: Regulatory oversight of multi-national clinical studies Ursula Kern, Advisory Committees Management Director, Federal Institute for Drugs and Medical Devices, Germany

2. Pooling patients in international multicenter studies is highly desirable in order to –speed up development in pediatric oncology –reduce costs –avoid duplication should have a solid basis in common ICH (International Conference on Harmonization) guidelines –unified quality standards (Good Clinical Practice) –harmonized ethical standards –unified guidelines for safety management requirements –unified scientific standards (e.g. role of statistical expertise)

3. German legislation in the framework of European legislation (1) National legislation has to follow the new and legally binding Clinical Trial Directive 2001/20/EC and Detailed Guidelines of the European Parliament and of the Council of the European Union. These Detailed Guidelines are binding as well and refer to (among others) –the application for an ethics committee opinion –request to competent authorities for authorization of a clinical trial –adverse reaction reporting obligations –inspection procedures and the qualification of inspectors The national Drug Law is being modified right now in order to comply with this Directive.

4. German legislation in the framework of European legislation continued (2) It is the intention of the Directive to prevent repetitive tests - whether within the Community or in third countries. ICH is explicitly mentioned as an appropriate forum for discussion in order to reach this aim. It is a further aim to simplify and harmonize rules on commencement of trials and to establish transparent procedures and effective communication between the parties involved. Clinical trial authorization will (as a rule) be implicit on the basis of the vote of an ethics committee (one single opinion per MS).

5. German legislation in the framework of European legislation continued (3) Ethics committees judge about the suitability of the trial protocol, the investigators, recruitment procedures, and the Informed Consent. Nevertheless, the competent authority may inform the sponsor of any grounds for non- acceptance. Protection of trial subjects includes insurance to cover the liability of the sponsor and the investigator. Clinical trials on children require at least some direct benefit for the group of patients concerned. The ethics committee has to have pediatric expertise. Exchange of information will include the establishment of an European database.

6. The implementation of the European Clinical Trial Directive means an supreme effort to promote multinational studies. However: there is considerable resistance. Some clinical investigators feel it is the death of academic trials. A responsibility shared by two of the main stakeholders in pediatric medicine development: - The regulatory authorities - The research-based industry Slide shown at a recent conference on drug development in children in Brussels

7. Investigator-driven trials in pediatric oncology: a development without regulatory oversight? There is an urgent need to apply new medicinal products in children with cancer and to develop new treatment regimen. Oncology products are widely used off-label in children. There is a widespread lack of interest on part of the pharmaceutical industry to act as a sponsor. Pediatric oncologists have taken the initiative and have developed a system of cooperative study groups with standard treatment protocols. There are many financial constraints and a lack of funding. The progress is undeniable: cure rates improved considerably However: These studies frequently deviate from regulatory requirements. clinicians feel over-regulated, and the implementation of the GCP Directive is considered „the death of academic trials“ by many investigators

8. Pediatric oncology studies - do they bypass regulatory oversight? Usual terminology –phase I, II, III, IV studies –exploratory vs. confirmatory studies –(non-interventional Studies) Pediatric oncology –„approval“ studies vs. „therapeutic“ studies“, „therapy optimization studies“ –commercial vs. non-commercial

9. The challenge: Can there be supranational networks of excellence for studies in pediatric oncology? - Thesis - There are no two classes of studies for which different criteria apply („approval“ vs. „therapeutic“ studies). Investigators willing to participate in multinational studies will have to accept this without feeling „over-regulated“. Regulatory oversight includes oversight over compliance with the EU Clinical Trial Directive. Conflicts between the clinical investigators‘ perspective and the regulatory perspective are obvious. Practical difficulties can be expected as the implementation means a modification of current practice and legislation.

10. The challenge: Supranational networks of excellence - Core principles - Detailed guidance on adverse reaction reporting is essential and available. Key elements are –the institution of an Independent Data and Safety Monitoring Committee for trials in high mortality disease states (continuing review of risks and expected benefits, necessary revisions of Informed Consent, decisions concerning stopping rules) –adverse event reporting, expedited reporting and notification of SUSARs Trial protocols should follow highest methodological standards. Regulatory oversight should start with Scientific Advice. „Non-approvable“ decisions often originate from study protocol deficiencies.