Dynamics of Search Spaces in the Drug Development Process of Alzheimer's Disease

Abstract

Alzheimer’s Disease (AD) forms one of the biggest global public health and social care challenges. Although a lot of research has been done on potential drug targets for AD after its identification in 1906 by Alois Alzheimer, there are still no treatments available to cure or halt the progression of AD. The failure of the drug development process is argued to be the result of a misalignment between scientific domains of fundamental research, preclinical research, and clinical research with deficiencies in the characterization of the disease, choice of therapeutic targets, and design of preclinical and clinical studies. This study explored the knowledge-based dynamics of these scientific domains, from the identification of AD in 1906 up to 2016, to provide a better understanding of the drug development process of AD. The aim of the study was to explain the evolution and relation of the knowledge bases of the three scientific domains. A theoretical framework was build based on the medical innovation literature and the triple helix model, wherein the knowledge bases were conceptualized as separate search spaces, defined as a cognitive framework for the definition of problems and identification of solutions. The dynamics of the fundamental, preclinical and clinical search spaces were proposed to be influenced by the interactions between the three search spaces, by the use of techniques (animal models and human clinical assessment tools) and by issued regulatory guidelines. Bibliometric analyses, including main path analysis (MPA), direct citation analysis, and co-word analysis were performed to assess the dynamics and interactions of the fundamental, preclinical and, clinical search space, and the influence of techniques and regulations. Additionally, an expert interview was conducted to support and validate the bibliometric analyses. This study has shown that the fundamental search space has predominantly influenced the dynamics and evolution of the preclinical and clinical search space, with the alignment of the search spaces toward the dominant view of the amyloid cascade hypothesis. In addition, in a disease with an unknown etiology, a new definition of the disease has a major impact on the search spaces involved in drug development. Moreover, this study has shown that there are multiple lines of research in the fundamental domain, especially in most recent years, which highlights that an avenue to the treatment of AD could be reached.