Description:

The burgeoning field of pharmacogenomics holds the promise to uncover genetic risk factors for both rare and common diseases, identify genetically based inter-individual responses to medicines, and enrich clinical trials with more genetically homogeneous groups, with the overarching goal to provide safer and more effective medicines to individuals and populations. With the sequencing of the human genome at the turn of the twentieth century, this last decade has seen an explosion in the development of technologies and methods to advance our understanding of the genetic underpinnings of disease and how individuals respond to medicines. In the field of Alzheimer’s disease research, pharmacogenomics has provided insight into the genetic complexity of this common disorder, confirming ApoE carrier status as a genetic determinant of risk for this disease, as well as identifying many other possible gene candidates. Recognition of global genetic diversity, however, requires that these methods be applied to different ethnic and racial groups throughout the world. Collaborations between academia, non-government organizations, and the pharmaceutical industry under the guidance and regulation of government-directed institutes and initiatives have been created in underdeveloped and developing countries in Africa, Asia, and Central and South America to identify unique genetic variation that will guide the development and use of medicines in these populations. Though each local population and government has its own set of economic, social, legal, regulatory and ethical challenges, the overarching goal in this endeavor is the translation of pharmacogenomic knowledge into the development of safer and more effective medicines for patients throughout the world.

Decades ago, pharmacogenetic research established that one’s genetic profile might predict efficacy and safety of medicines. Polymorphic expression of isoenzymes of the cytochrome P-450 enzyme system explains a significant amount of the variability of inter-individual responses to medicines. In Alzheimer’s disease, the highly variable clinical response to cholinesterase inhibitors metabolized by the liver is explained on this basis. More recently, translation of basic pharmacogenomic research through the drug development process has led to the approval of ”personalized“ medicines, for example, in the field of oncology, cardiology and psychiatry, based on an individual’s underlying genotypic variance of phenotypically expressed pathogenic targets and pathways. Translational pharmacogenomic research in Alzheimer’s disease has emerged as a viable alternative to the study of large populations with similar phenotypic expression of symptoms through stratification of sub-groups based on ApoE carrier status in clinical trials. When initiating a global research protocol, it is incumbent upon sponsors to actively engage stakeholders in developing and underdeveloped countries, including local government authorities, regulatory bodies, ethics review boards, community representatives and participants, to address all aspects of the clinical trial, especially informed consent, which may be more challenging in countries where local customs and practices dictate the need for innovative approaches. Implementation of pharmacogenomics in the clinical trial requires further attention to ethical detail related to what kind of informed consent is needed for use of stored DNA samples for future, unforeseen related or unrelated research, whether and to whom to disclose current and future study results, and ways by which the benefits of current and future discoveries are shared by stakeholders in developed and underdeveloped or developing countries.