Successes Achieved and Challenges Ahead in Translating Biomarkers into Clinical Applications

Biomarkers are important tools for identifying and stratifying diseases, predicting their progression and determining the effectiveness, safety, and doses of therapeutic interventions. This is important for common chronic diseases such as diabetic nephropathy, osteoporosis, and rheumatoid arthritis which affect large numbers of patients worldwide. This article summarizes the current knowledge of established and novel biomarkers for each of these diseases as presented at the 2008 AAPS/ACCP joint symposium “Success Achieved and Challenges Ahead in Translating Biomarkers into Clinical Applications,” in Atlanta, Georgia. The advantages and disadvantages of various proteomic, metabolomic, genomic, and imaging biomarkers are discussed in relation to disease diagnosis and stratification, prognosis, drug development, and potential clinical applications. The use of biomarkers as a means to determine therapeutic interventions is also considered. In addition, we show that biomarkers may be useful for adapting therapies for individual needs by allowing the selection of patients who are most likely to respond or react adversely to a particular treatment. They may also be used to determine whether the development of a novel therapy is worth pursuing by informing crucial go/no go decisions around safety and efficacy. Indeed, regulatory bodies now suggest that effective integration of biomarkers into clinical drug development programs is likely to promote the development of novel therapeutics and more personalized medicine.     

Training Community-Based Clinicians in Screening and Brief Intervention for Substance Abuse Problems: Translating Evidence into Practice

Screening and brief intervention in general health care settings are efficacious but have not been widely adopted. Our objective was to assess the effect of an educational intervention on clinicians' substance abuse-related clinical practices. The study was a telephone survey of practicing physicians, nurses, psychologists, physician's assistants, and social workers who attended a half-day continuing education course on one of four occasions. The course covered the stages of behavioral change and motivational counseling, using primarily role play with standardized patients. Of 87 course attendees, 70 (80%) completed the interview. Months to years after the course, most (91%) reported that the course made an impact on their practice. Most (78%) of respondents reported that they frequently or always asked new patients who drank alcohol a formal screening questionnaire such as the CAGE, and 94% frequently or always assessed their substance abusing patients' readiness to change. Most respondents reported that since taking the course they were more likely (1) to screen patients for alcohol or drug related problems (86%) and (2) to ask patients about their substance abuse on a follow-up visit (96%). After exposure to an active-learning half-day continuing education course, clinicians reported improvement with and high rates of desirable substance abuse-related clinical practices up to 5 years later. Continuing education efforts that incorporate active learning directed toward practicing clinicians show promise for improving rates of brief intervention for alcohol and other drug abuse.     

Translating RNA interference into therapies for human disease

RNA interference (RNAi) represents one of the most promising new frontiers in drug discovery. Breakthroughs in understanding RNA's extensive natural role in essential cellular processes have opened up the potential for a whole new class of drugs based on RNAi. Harnessing the natural process of RNAi, short, double-stranded RNA molecules are able to inhibit expression of genes in a sequence-specific manner. By targeting disease-causing genes, RNAi drugs have the potential to be more selective than traditional drugs, and thus more effective as well as less toxic. Over the past few years, important strides have been made in translating the promise of RNAi into therapies for human disease. In contrast to the extensive lead optimization steps typically required in small-molecule and protein drug discovery, RNAi drug candidates can be identified using bioinformatics to select sequences complementary to the target mRNA. The process of selecting an RNAi-based drug candidate may simply involve the synthesis and testing of a relatively small number of short double strands (duplexes) of RNA, incorporating chemical modifications that confer stability and direct these RNA duplexes to the appropriate tissues and cells, and/or formulating these RNA duplexes with appropriate delivery agents to achieve the same goals. As advances in RNAi therapeutics continue, the decades to come should bring a potent new class of drugs based on RNAi.     

The 6th Drug Discovery for Neurodegeneration Conference: An Intensive Course on Translating Research into Drugs

Neurodegenerative disorders are rapidly becoming one of the greatest unmet health needs. This annual workshop facilitates innovation and progress in neurodegenerative disease drug discovery by convening stakeholders from charitable foundations, government, academia and industry who introduce scientists to the drug development and approval process. New to the 2012 workshop were candid discussions about re-visiting the CNS therapeutic development process. The continuing challenge is partly due to the poor forecasting potential of models of CNS diseases, as well as the lack of reproducibility of published studies, and greater need to increase focus on pharmacodynamic end points. Significant discussion centered on how to improve discovery approaches using examples of recent successes in the field. For example, the idea of combining reductionist, single-target strategies with functional-approach logic was suggested by several speakers, and widely discussed in the workshop. The didactic aspects of the workshop highlighted underlying concepts, best practices and trends that have characterized successful campaigns. The technical and scientific guidance was complemented by discussions of practical ways to approach the major funding gaps required for translation of projects from basic science to clinical investigations. This workshop has evolved to serve a critical educational need, with a wide range of investigator participation.