The scientific community has been enthusiastic about DNA microarray technology for pharmacogenomic and toxicogenomic studies in the hope of advancing personalized medicine and drug development. The ...US Food and Drug Administration has been proactive in promoting the use of pharmacogenomic data in drug development and has issued a draft guidance for the pharmaceutical industry on data submissions. However, many challenges and pitfalls are facing the microarray community and regulatory agencies before microarray data can be reliably applied to support regulatory decision making. Four types of factors (i.e., technical, instrumental, computational and interpretative) affect the outcome of a microarray study, and a major concern about microarray studies has been the lack of reproducibility and accuracy. Intralaboratory data consistency is the foundation of reliable knowledge extraction and meaningful crosslaboratory or crossplatform comparisons; unfortunately, it has not been seriously evaluated and demonstrated in every study. Profound problems in data quality have been observed from analyzing published data sets, and many laboratories have been struggling with technical troubleshooting rather than generating reliable data of scientific significance. The microarray community and regulatory agencies must work together to establish a set of consensus quality assurance and quality control criteria for assessing and ensuring data quality, to identify critical factors affecting data quality, and to optimize and standardize microarray procedures so that biologic interpretation and decision-making are not based on unreliable data. These fundamental issues must be adequately addressed before microarray technology can be transformed from a research tool to clinical practices.
A series of questions about hypothetical drugs and pharmacogenomic tests was posed to a panel of representatives from the health plan, government and employer sectors in order to elicit suggestions ...for input on data or study design considerations important for coverage determination. The panel suggested seven areas for drug developers to strongly consider. These areas were to include comparative information on new tests versus usual care, assess the negative predictive value of new tests, measure and report on cost offsets, balance relative risk improvement with absolute risk, consider the policy implications of the products or tests, report percentage responders in addition to group mean improvements, and to include specific pharmacogenomic information in US FDA approved labels. The panel was generally enthusiastic about the promise of the field to improve drug selection or dosing.
The drug development process is dependent upon having established end points for measuring drug efficacy and adverse effects. New drug development in organ transplantation suffers from having end ...points which are either outdated or which do not serve the purpose of addressing the current critical drug therapy problems. Numerous biomarkers have been examined in organ transplantation, but almost all would be classified as exploratory for drug development purposes. Some of the possible pathways out of this dilemma include investigator‐ or consortium‐initiated research that would qualify the biomarkers as either probable or known valid biomarkers, help in identification of new end points in transplantation and their associated biomarkers, co‐development of a new biomarker and drug for transplantation and the use of new clinical trial design methods which facilitate enriched or stratified transplant patient populations. With new biomarkers and new study design methodologies for drug development, improvement in the drug development process for transplantation is a real possibility that the transplant clinical and research community can help to bring about.
FDA‐qualified biomarkers are badly needed for drug development in transplantation, and multiple mechanisms exist for transplant clinicians and researchers to contribute to the qualification process.
Over the last decade, the introduction of microarray technology has had a profound impact on gene expression research. The publication of studies with dissimilar or altogether contradictory results, ...obtained using different microarray platforms to analyze identical RNA samples, has raised concerns about the reliability of this technology. The MicroArray Quality Control (MAQC) project was initiated to address these concerns, as well as other performance and data analysis issues. Expression data on four titration pools from two distinct reference RNA samples were generated at multiple test sites using a variety of microarray-based and alternative technology platforms. Here we describe the experimental design and probe mapping efforts behind the MAQC project. We show intraplatform consistency across test sites as well as a high level of interplatform concordance in terms of genes identified as differentially expressed. This study provides a resource that represents an important first step toward establishing a framework for the use of microarrays in clinical and regulatory settings.
Regulatory Acceptance of Toxicogenomics Data Frueh, Felix W.; Huang, Shiew-Mei; Lesko, Lawrence J.
Environmental health perspectives,
08/2004, Volume:
112, Issue:
12
Journal Article
The qualification of biomarkers of drug safety requires data on many compounds and nonclinical and clinical studies. The cost and effort associated with these qualifications cannot be easily covered ...by a single pharmaceutical company. Intellectual property associated with safety biomarkers is also held by many different companies. Consortia between different pharmaceutical companies can overcome cost and intellectual property hurdles to biomarker qualification. The Predictive Safety Testing Consortium (PSTC) is a collaborative effort between 16 different pharmaceutical companies to generate data supporting biomarker qualification. This Consortium is coordinated through the C-Path Institute, and currently has five biomarker qualification working groups engaged in this collaboration: nephrotoxicity, hepatotoxicity, vascular injury, myopathy, and non-genotoxic carcinogenicity. These working groups are aided by a data management team and a translational strategy team. Qualification studies of promising biomarkers are already progressing in several of the working groups, and results in the nephrotoxicity working group warranted a data submission to the FDA and EMEA for regulatory qualification of new nephrotoxicity biomarkers.
Janet Woodcock – Food and Drug Administration, Rockville, MD, USA
This work describes the in situ synthesis of oligonucleotide arrays on glass surfaces. These arrays are composed of features defined and separated by differential surface tension (surface tension ...arrays). Specifically, photolithographic methods were used to create a series of spatially addressable, circular features containing an amino-terminated organosilane coupled to the glass through a siloxane linkage. Each feature is bounded by a perfluorosilanated surface. The differences in surface energies between the features and surrounding zones allow for chemical reactions to be readily localized within a defined site. The aminosilanation process was analyzed using contact angle, X-ray photoelectron spectroscopy (XPS), and time-of-flight/secondary ion mass spectroscopy (TOF-SIMS). The efficiency of phosphoramidite-based oligonucleotide synthesis on these surface tension arrays was measured by two methods. One method, termed step-yields-by-hybridization, indicates an average synthesis efficiency for all four (A,G,C,T) bases of 99.9 ± 1.1%. Step yields measured for the individual amidite bases showed efficiencies of 98.8% (dT), 98.0% (dA), 97.0% (dC), and 97.6% (dG). The second method for determining the amidite coupling efficiencies was by capillary electrophoresis (CE) analysis. Homopolymers of dT (40- and 60mer), dA (40mer), and dC (40mer) were synthesized on an NH4OH labile linkage. After cleavage, the products were analyzed by CE. Synthesis efficiencies were calculated by comparison of the full-length product peak with the failure peaks. The calculated coupling efficiencies were 98.8% (dT), 96.8% (dA), and 96.7% (dC).
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