Identification of platform-independent gene expression markers of cisplatin nephrotoxicity.

Within the International Life Sciences Institute Committee on Genomics, a working group was formed to focus on the application of microarray technology to preclinical assessments of drug-induced nephrotoxicity. As part of this effort, Sprague-Dawley rats were treated with the nephrotoxicant cisplatin at doses of 0.3-5 mg/kg over a 4- to 144-hr time course. RNA prepared from these animals was run on a variety of microarray formats at multiple sites. A set of 93 differentially expressed genes associated with cisplatin-induced renal injury was identified on the National Institute of Environmental Health Sciences (NIEHS) custom cDNA microarray platform using quadruplicate measurements of pooled animal RNA. The reproducibility of this profile of statistically significant gene changes on other platforms, in pooled and individual animal replicate samples, and in an independent study was investigated. A good correlation in response between platforms was found among the 48 genes in the NIEHS data set that could be matched to probes on the Affymetrix RGU34A array by UniGene identifier or sequence alignment. Similar results were obtained with genes that could be linked between the NIEHS and Incyte or PHASE-1 arrays. The degree of renal damage induced by cisplatin in individual animals was commensurate with the number of differentially expressed genes in this data set. These results suggest that gene profiles linked to specific types of tissue injury or mechanisms of toxicity and identified in well-performed replicated microarray experiments may be extrapolatable across platform technologies, laboratories, and in-life studies

Use of a mixed tissue RNA design for performance assessments on multiple microarray formats

The comparability and reliability of data generated using microarray technology would be enhanced by use of a common set of standards that allow accuracy, reproducibility and dynamic range assessments on multiple formats. We designed and tested a complex biological reagent for performance measurements on three commercial oligonucleotide array formats that differ in probe design and signal measurement methodology. The reagent is a set of two mixtures with different proportions of RNA for each of four rat tissues (brain, liver, kidney and testes). The design provides four known ratio measurements of >200 reference probes, which were chosen for their tissue-selectivity, dynamic range coverage and alignment to the same exemplar transcript sequence across all three platforms. The data generated from testing three biological replicates of the reagent at eight laboratories on three array formats provides a benchmark set for both laboratory and data processing performance assessments. Close agreement with target ratios adjusted for sample complexity was achieved on all platforms and low variance was observed among platforms, replicates and sites. The mixed tissue design produces a reagent with known gene expression changes within a complex sample and can serve as a paradigm for performance standards for microarrays that target other species

emerging technologies for food and drug safety

Abstract Emerging technologies are playing a major role in the generation of new approaches to assess the safety of both foods and drugs. However, the integration of emerging technologies in the regulatory decision-making process requires rigorous assessment and consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) in partnership with the Brazilian Health Surveillance Agency (ANVISA) hosted the seventh Global Summit on Regulatory Science (GSRS17) in Brasilia, Brazil on September 18–20, 2017 to discuss the role of new approaches in regulatory science with a specific emphasis on applications in food and medical product safety. The global regulatory landscape concerning the application of new technologies was assessed in several countries worldwide. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the development, application and review of emerging technologies. The need for advanced approaches to allow for faster, less expensive and more predictive methodologies was elaborated. In addition, the strengths and weaknesses of each new approach was discussed. And finally, the need for standards and reproducible approaches was reviewed to enhance the application of the emerging technologies to improve food and drug safety. The overarching goal of GSRS17 was to provide a venue where regulators and researchers meet to develop collaborations addressing the most pressing scientific challenges and facilitate the adoption of novel technical innovations to advance the field of regulatory science

Alternative Mouse Models for Future Cancer Risk Assessment

*This commentary was created by members of the limited duration key issues team that supports the representatives of the Pharmaceutical Research and Manufacturers Association on the ICH S1 Expert Working Group. This is an opinion article submitted to the Regulatory Forum and does not constitute an official position of the Society of Toxicologic Pathology or the journal Toxicologic Pathology. The views expressed in this article are those of the authors and do not necessarily represent the policies, positions or opinions of their respective agencies and organizations. The Regulatory Forum is designed to stimulate broad discussion of topics relevant to regulatory issues in toxicologic pathology. Readers of Toxicologic Pathology are encouraged to send their thoughts on these articles or ideas for new topics to [email protected]

A systematic approach to preclinical and clinical safety biomarker qualification incorporating Bradford Hill’s principles of causality association

A number of pharmaceutical companies have become involved in exploring novel safety biomarkers based on the premise that improved predictors or earlier reporters of toxicity events will reduce the rate of drug attrition and repurpose resources to other improvements in R&D. Until recently, advances in safety biomarker research have lagged behind advances in efficacy-based biomarkers used in drug discovery and development. There are currently a number of pharmaceutical-academic-regulatory collaborations e.g. the C-Path Institute’s Predictive Safety Testing Consortium (PSTC), the Health and Environmental Sciences Institute (HESI-US), The International Life Sciences Institute (ILSI-worldwide) and Innovative Medicine Inititative’s Safer And Faster Evidence-based Translation consortium (IMI SAFE-T) aim to foster collective knowledge in the qualification of novel safety biomarkers to reduce new chemical entity attrition rates. While this is a laudable goal, scientific processes and appropriate standards for ‘prioritising’, ‘validating’ and ‘qualifying’ or candidate biomarkers are not clearly established and recognised. The recent FDA/EMEA guidelines on qualification of biomarkers are an important step in the regulatory processes of biomarker qualification1. Still, there are a number of unanswered concerns regarding what constitutes a useful biomarker with added value to historical biomarkers and what are the optimal ways of collecting and evaluating scientific evidence for the clinical qualification of a biomarker. The focus of this publication is to provide clarity on what is meant by the prioritisation and qualification of biomarker candidates. It is proposed that the well-known concept of Bradford Hill’s causality association criteria could be applied as a general framework for this purpose. Sir Austin Bradford Hill established the following nine criteria for causation (does factor A cause disorder B) to separate the causal and non-causal mechanisms of the observed associations. Although developed for use in the field of occupational medicine, these criteria (strength of association, consistency, temporality, biological gradient, plausibility, coherence, specificity, experimental evidence and analogy) can be used in many situations to establish causal relationships and we are proposing that Hill’s criteria offer a useful approach to aid the qualification of safety biomarkers