Masterstudiengang "Drug Regulatory Affairs"


Clinical development of a new chemical entity compared to a somatic cell therapy product for Parkinson´s disease in the regulatory framework of the EU

Dr. med. Klaus Eckhardt (Abschlußjahr: 2004)

This thesis presents the implications of recent changes within the regulatory framework of the EU on the preclinical and clinical development processes especially focussing on the new annex 1 (2003/63/EC) and the Clinical Trial Directive 2001/20/EC. The procedures involving authorisation by the competent authority, the evaluation by the ethics committees and pharmacovigilance of clinical trials after the implementation of 2001/20/EC into the German Drug Law are described.

Furthermore the regulatory requirements for the preclinical and clinical development of different types of investigational medicinal products exemplified for the treatment of Parkinson´s disease are presented. An innovative somatic cell therapy medicinal product is compared with a conventional pharmaceutical with neuroprotective properties.

Concerning the preclinical studies for conventional pharmaceuticals the multidisciplinary guidance CPMP/ICH/286/95 provides detailed recommendations for pharmacodynamic, pharmacokinetic and especially the different types of toxicity studies required for clinical studies in humans. In contrast to the established regulatory requirements specified conventional pharmaceuticals, for the innovative somatic cell therapy products the regulatory required preclinical studies are not laid down in detail. Due to important differences to conventional pharmaceuticals, e.g. species specifity and permanent administration, preclinical studies on somatic cell therapy products focus on immunogenic reactions, survival of transplanted cells.

Also the clinical development of a somatic cell therapy product will be substantially different compared to the classical clinical development of a conventional pharmaceutical. The clinical development of a conventional pharmaceutical consists of the classical three phases involving human pharmacology in healthy volunteers, exploratory and confirmatory studies in patients. and in classical dose finding studies. However, for a dopaminergic neuronal cell product the clinical development program will be reduced because human pharmacology studies in healthy volunteers of the permanent administration are not feasible due to ethical and scientific reasons.

For advanced therapy medicinal products preclinical and clinical development programs should be set up on a case by case basis due to the lack of experience. As the regulatory requirements for somatic cell therapy products are not well established the scientific advice procedure offered by the EMEA is recommended providing the opportunity to present and discuss the development program. This is especially important because according to the new regulation 724/2004/EC all medicinal products developed for the treatment of Parkinson´s disease will have to be authorised within in the centralised procedure at the EMEA.

While drug development for conventional pharmaceuticals is well established and is based on detailed guidance documents, the development of somatic cell therapy requires the use of innovative methods, e.g. pharmacogenomics and DNA microarrays. This thesis presents further topics which could facilitate and improve drug development like modeling and simulation methods and statistical considerations. In addition the ethical concerns concerning the use of sham surgery in clinical trials investigating somatic cell therapy products in Parkinson´s disease are discussed. Integrating innovations from basic science into the regulatory procedures could accelerate and improve the translation of basic science into drug development. Improving and facilitating the preclinical and clinical development of advanced therapy medicinal products like dopaminergic cell therapy could provide a much needed improvement in the treatment of Parkinson´s disease by restoring dopaminergic function.

Pages: 82