Identification and Elucidation of the Biology of Adverse Events: The Challenges of Safety Assessment and Translational Medicine

Abstract

There has been an explosion of technology-enabled scientific insight into the basic biology of the causes of adverse events. This has been driven, in part, by the development of the various "omics" tools (e.g., genomics, proteomics, and metabolomics) and associated bioinformatics platforms. Meanwhile, for decades, changes in preclinical testing protocols and guidelines have been limited. Preclinical safety testing currently relies heavily on the use of outdated animal models. Application of systems biology methods to evaluation of toxicities in oncology treatments can accelerate the introduction of safe, effective drugs. Systems biology adds insights regarding the causes and mechanisms of adverse effects, provides important and actionable information to help understand the risks and benefits to humans, focuses testing on methods that add value to the safety testing process, and leads to modifications of chemical entities to reduce liabilities during development. Leveraging emerging technologies, such as genomics and proteomics, may make preclinical safety testing more efficient and accurate and lead to better safety decisions. The development of a U.S. Food and Drug Administration guidance document on the use of systems biology in clinical testing would greatly benefit the development of drugs for oncology by communicating the potential application of specific methodologies, providing a framework for qualification and application of systems biology outcomes, and providing insight into the challenges and limitations of systems biology in the regulatory decision-making process. Clin Cancer Res; 17(21); 6641-5. Ó2011 AACR. Introductory NoteAt the 2010 Conference on Clinical Cancer Research, co-convened by Friends of Cancer Research and the Engelberg Center for Health Care Reform at the Brookings Institution, participants explored 4 pressing new challenges in the field. Articles summarizing the panel's recommendations on each of these topics are featured in this issue of Clinical Cancer Research (1-4). Gaps in Current Testing and Safety Assessment ParadigmsThe toxicity of new oncology drugs is a leading cause of pharmaceutical attrition and a major impediment to efficient and successful drug development. Safety, or lack thereof, is also a major factor in regulatory decisions involving drug approval, labeling, risk evaluation, and mitigation and even withdrawal from the marketplace. The current battery of preclinical safety studies required to support the clinical development of new drugs and marketing approval is mapped out in International Conference on Harmonisation (ICH) guidelines that include ICH M3, E14, and S1 to S9 (5). In addition, various other documents from regulatory agencies provide recommendations regarding specific toxicities or adverse events, such as hepatotoxicity (6). However, these testing methods and risk assessments have not kept pace with the rapid evolution of technology, biomedical research, and knowledge generation. For example, the studies required to meet international regulatory...

Safety Biomarkers in Preclinical Development

“…These data-driven platforms have helped transform drug safety from being a subjective and observation-based discipline to one capable of defining the biologic basis of adverse events at the cellular, molecular, and biochemical levels. 89 The combination of ''omics'' data sets can provide a more thorough and efficient means to obtain insight into mechanisms of disease/toxicity, leading to the identification of novel disease biomarkers. 49 When ''omics'' are used either alone or better yet in conjunction with other technologies (systems biology approach), they can rapidly fill the gap in the development of new minimally invasive and easily accessible biomarkers in preclinical and clinical studies.…”

“…24,48,85 Systems biology is the combination of the ''omics'' platforms, bioinformatics, and other biologic data, which focuses on interactions within and between the mechanisms that combine to give rise to the function and behavior of a biological system. 34,89 Deciphering complex, highly networked, and pleiotropic pathways that give rise to adverse events aids in the identification of specific biomarkers, which ultimately helps us understand the patient risks and improves the overall safety testing process. 34,89 The leveraging of systems biology technologies may make preclinical safety testing more efficient and accurate, leading to better decisions on patient risk/benefit.…”

“…34,89 Deciphering complex, highly networked, and pleiotropic pathways that give rise to adverse events aids in the identification of specific biomarkers, which ultimately helps us understand the patient risks and improves the overall safety testing process. 34,89 The leveraging of systems biology technologies may make preclinical safety testing more efficient and accurate, leading to better decisions on patient risk/benefit. 89 Transcriptomics.…”

The Discovery of Cancer Tissue Specific Proteins in Serum: Case Studies on Prostate Cancer

“…This lack in analytical efficiency has often resulted in the erroneous assessment and derivation of biological indicators, or biomarkers, of prostate cancer disease (Balk, Ko, & Bubley, 2003;Thompson et al, 2005). The reasons for the ineffective utility of these biomarkers are multi-fold and include the following, (i) they lack specificity and selectivity to the cancer type of interest, (ii) their reproducible detection is poor, (iii) the sensitivity of available methods, especially as they refer to biological fluids such as serum and plasma, is poor relative to the natural abundance levels of the tissuespecific secreted or shedded molecular entities of disease, and (iv) the majority of the available analytical protocols measure biomarkers at the DNA and mRNA level, which may not reflect the phenotypic aspects of disease (Adewale et al, 2008;Buchen, 2011;Lin et al, 2005;Rahbar et al, 2011;Sawyers, 2008;Turteltaub et al, 2011). In addition, the availability of more selective prognosis strategies may also help identify patient cohorts, or even single individuals, eligible for adjuvant therapy (i.e., personalized medicine).…”

“…This especially becomes true when the complexity of the derived proteomes is decoded in the form of biological pathways and their networks that allow the interrogation of novel candidate protein markers as physiologic targets. Consequent to with this notion, the family of protein markers that will encompass the molecular biology of carcinogenesis will include not only tissue specific proteins but also proteins that reflect systemic changes that predispose a seemingly healthy individual to a longer-term initiation to event of carcinogenesis (Adewale et al, 2008;Buchen, 2011;DeMarzo et al, 2004;Hanahan & Weinberg, 2011;Joyce, 2005;Rahbar et al, 2011;Sawyers, 2008;Turteltaub et al, 2011). In addition to protein markers, and in particular enzyme species, other biological indicators of disease and its predisposition, may include co-factors (i.e., vitamin species) and protein end-products such as 1° and 2° metabolites in the form nucleic acids, amino acids, fatty acids and xenobiotic species in their parent and biotransformed moieties.…”