Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Drug Development and Critical Analysis of the Reliability of Preclinical Studies ***

Dr. Jennifer Anthöfer (Abschlußjahr: 2015)

Summary
Language: English
The aim of this master thesis is to give an overview of the drug development process with a particular focus on preclinical studies and their reliability concerning the translation from animal testing to clinical trials in humans. The thesis addresses the potential obstacles and biases which can occur during the translational process from preclinical research to clinical trials and, in addition, discusses possible improvement strategies.
Drug development can commonly be divided into four main pillars: Drug discovery, preclinical development, clinical studies and marketing authorisation of a newly found chemical entity. During the phase of drug discovery potential new targets for special diseases are identified and validated. After finding initial hit substances they are optimised in order to obtain so-called lead compounds. The most successful lead compounds found during the drug discovery program are then investigated in preclinical in vitro and in vivo studies. The main objective of the considerable number of preclinical studies is getting a better understanding of the toxicological profile of an individually tested substance. With the knowledge of toxic effects and pharmacological properties of the respective compound, it is attempted to establish a safe initial dose for first in man exposure in clinical Phase I trials. Preclinical studies are conducted before and even during clinical studies in order to ensure continuous monitoring. The most promising candidates determined during preclinical research are tested in clinical trials in order to analyse their human compatibility. The conduction of Phase I to Phase III clinical trials is a mandatory tool in order to have the opportunity to apply for a marketing authorisation for new medicinal products. Obtaining a marketing authorisation is necessary to place a medicinal product on the market and thereby make it accessible to the general public.
Well-conceived preclinical studies are a critical element of translational research and the subsequent successful marketing authorisation of a new medicinal product, thus making new, urgently needed medicinal products available to patients. However, this translational process may frequently be riddled with various hurdles which need to be overcome. Shortcomings in in vitro analyses of a compound like intra-laboratory cell line heterogeneity or a lack of quality control and quality assurance may be major issues. Furthermore, investigator bias and a potential lack of scientific rigor play important roles concerning the poor predictability of a lot of preclinical studies. Special guidance like the Good Laboratory Practice (GLP), adequate training and the supervision of scientists should therefore be essential requirements in order to receive validity of the study results. Potential weaknesses in the design, conduction and analysis of preclinical studies may be overcome by adopting standards similar to those applied in clinical trials, e.g. realising tools like randomisation and blinding or having placebo controls. Another important point all participants (investigators, publisher, clinical staff, etc.) should be aware of, is the fact that the animals used in preclinical studies are only models for special human diseases which in most cases cannot reflect the complexity of the particular disease. Special validity scoring systems allow compilation of a combination of animal models and may reach maximal validity, therefore coming closer to the clinical situation. Apart from weaknesses in the design, conduction and analysis of preclinical studies and reduced external validity due to disparities between animal models and humans, a systematic problem exists which is assumed to play a major role for the reliability of preclinical studies. Nowadays, the number and the impact of publications are considered to be key drivers for a successful career in science. By looking for excellent results, publication bias is encouraged and inevitably leads to an overestimation of treatment findings. Tolerating and giving incentives for fast publications of excellent stories is frequently combined with poor quality and non-validated methods or analyses. The system has to change in a way whereas only publications of validated preclinical studies conducted and analysed with high quality standards as used in clinical trials should be supported. Furthermore, attention should also be given to negative outcomes as learning from these findings can possibly minimise unnecessary in vitro and animal studies.
Pages: 57