Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Biomarkers in preclinical and clinical research: definitions, identification, applications, validation and qualification processes at the FDA and EMA ***

Andreas Försch (Abschlußjahr: 2010)

Language: English

The number of new drugs approved each year has been declining for several years, while the total research and development costs to bring a new drug to market have been drastically increasing. Many compounds fail in late stages, resulting in enormous expenses, such as failing phase III trials, due to lack of efficacy and toxicity. The path to market, even for successful compounds is long, costly and inefficient, due to sometimes cumbersome methods of assessing efficacy and safety. To address these issues, both the EMA and the FDA are establishing new methods and processes to help facilitate drug development. The application of biomarkers in preclinical and clinical studies is considered by both the EMA and the FDA as an important method to reduce costs and speed up the development process.

In this thesis an overview of current applications of biomarkers both in preclinical and clinical research is provided, biomarker identification methods are presented and the current regulatory initiatives at the FDA and EMA to qualify biomarkers are discussed.

In the beginning, different biomarker definitions and categories, such as dose-selection-, patient selection-, toxicity- and mechanism-biomarkers are introduced. Then, with the help of different examples of biomarkers used in preclinical studies, possibilities to improve toxicity and risk assessment are demonstrated. In this context, a panel of nephrotoxicity biomarkers, accepted by both the EMA and the FDA in 2008 as qualified for preclinical drug evaluation trials is discussed. Further, a range of biomarkers for the prediction of drug induced liver injury, currently being evaluated by different consortia, are presented. Additionally, the thesis highlights different examples of biomarkers used in clinical development and shows the advantages of the effective use of biomarkers in clinical registration trials.

To identify biomarkers, different methods based on molecular profiling techniques, such as genetics, transcriptomics, proteomics and metabolomics are available. The advantages and limitations of each approach are discussed and examples of their application are given.

Moreover, in order to apply any biomarker in drug development studies, a thorough validation of a biomarkers performance is obligatory. It is important that this validation is “fit-for-purpose” to meet the individual study objectives. The validation process needs to be iterative with regard to the intended use of the biomarker in the development process.

Qualification then goes one step beyond validation. Through a qualification program, the biomarker is linked with biological processes and clinical or disease endpoints. An official regulatory qualification ensures that data generated with biomarkers in drug development studies is later accepted by regulatory agencies. Therefore, the EMA and FDA recently established new processes to allow a regulatory qualification of biomarkers that are intended to be applied in drug registration trials. A thorough overview of these processes is provided.

The thesis concludes with a summary of the advantages of biomarker applications in drug development and an outlook on future developments.

Pages: 58, Annexes: 2, pages: 4