A number of publications have reported the use of microarray technology to identify gene expression signatures to infer mechanisms and pathways associated with systemic lupus erythematosus (SLE) in ...human peripheral blood mononuclear cells. However, meta-analysis approaches with microarray data have not been well-explored in SLE.
In this study, a pathway-based meta-analysis was applied to four independent gene expression oligonucleotide microarray data sets to identify gene expression signatures for SLE, and these data sets were confirmed by a fifth independent data set.
Differentially expressed genes (DEGs) were identified in each data set by comparing expression microarray data from control samples and SLE samples. Using Ingenuity Pathway Analysis software, pathways associated with the DEGs were identified in each of the four data sets. Using the leave one data set out pathway-based meta-analysis approach, a 37-gene metasignature was identified. This SLE metasignature clearly distinguished SLE patients from controls as observed by unsupervised learning methods. The final confirmation of the metasignature was achieved by applying the metasignature to a fifth independent data set.
The novel pathway-based meta-analysis approach proved to be a useful technique for grouping disparate microarray data sets. This technique allowed for validated conclusions to be drawn across four different data sets and confirmed by an independent fifth data set. The metasignature and pathways identified by using this approach may serve as a source for identifying therapeutic targets for SLE and may possibly be used for diagnostic and monitoring purposes. Moreover, the meta-analysis approach provides a simple, intuitive solution for combining disparate microarray data sets to identify a strong metasignature.
Study Objectives. To review the labels of United States Food and Drug Administration (FDA)‐approved drugs to identify those that contain pharmacogenomic biomarker information, and to collect ...prevalence information on the use of those drugs for which pharmacogenomic information is included in the drug labeling.
Design. Retrospective analysis.
Data Sources. The Physicians' Desk Reference Web site, Drugs@FDA Web site, and manufacturers' Web sites were used to identify drug labels containing pharmacogenomic information, and the prescription claims database of a large pharmacy benefits manager (insuring > 55 million individuals in the United States) was used to obtain drug utilization data.
Measurements and Main Results. Pharmacogenomic biomarkers were defined, FDA‐approved drug labels containing this information were identified, and utilization of these drugs was determined. Of 1200 drug labels reviewed for the years 1945–2005, 121 drug labels contained pharmacogenomic information based on a key word search and follow‐up screening. Of those, 69 labels referred to human genomic biomarkers, and 52 referred to microbial genomic biomarkers. Of the labels referring to human biomarkers, 43 (62%) pertained to polymorphisms in cytochrome P450 (CYP) enzyme metabolism, with CYP2D6 being most common. Of 36.1 million patients whose prescriptions were processed by a large pharmacy benefits manager in 2006, about 8.8 million (24.3%) received one or more drugs with human genomic biomarker information in the drug label.
Conclusion. Nearly one fourth of all outpatients received one or more drugs that have pharmacogenomic information in the label for that drug. The incorporation and appropriate use of pharmacogenomic information in drug labels should be tested for its ability to improve drug use and safety in the United States.
The traditional route for regulatory acceptance of biomarkers in drug development is through submission of biomarker data in drug approval submissions in the context of a single drug development ...program. The US FDA's Critical Path Initiative called for establishment of a biomarker qualification process to enable progress in the drug development paradigm. In response to this, the Center for Drug Evaluation and Research (CDER) established a Biomarker Qualification Program (BQP) to qualify a biomarker for a specific context of use (COU). The qualified biomarker can then be used in multiple drug development programs for this COU without re-review. Here, we describe some of the features of the BQP and two new initiatives that have the potential to aid biomarker development through early interactions with the FDA. Finally, we discuss some of the feedback the FDA has received from submitters and the BQP's actions to strengthen the program.
Abstract Autoimmune diseases (AIDs) are believed to be multifactorial diseases that commonly involve multiple organ systems. About three fourth of the patients afflicted with AIDs are women ...suggesting that sex differences impact the incidence of AID. However, the proportion of females to males suffering from AID varies depending on the disease. The response to some AID therapeutics also differs in females versus males, suggesting that enrollment of adequate numbers of women and men is important in clinical trials for development of AID drugs. It is known for a long time that genetic factors are important contributors to AID susceptibility. Currently available information suggests that multiple genes with modest association to AID contribute to susceptibility to AID. Also, the associations may differ for the various ethnicities. The major histocompatibility (MHC) locus appears to be a major genetic factor that confers susceptibility to multiple AIDs, even though the locus is complex and has the highest density of genes in the human genome. Thus, the association of different AIDs could be with different genes in the MHC locus. Among the non-MHC genes, some of the risk alleles are shared between different AIDs, but may not be common to all AIDs. For example, genetic polymorphisms in the Protein Tyrosine Phosphatase-22 ( PTPN22) gene have reproducibly shown to have association with systemic lupus erythematosus (SLE), Graves’ disease (GD), rheumatoid arthritis (RA) and multiple sclerosis (MS), but not with psoriasis. Identification of factors responsible for risk for developing AID and the of the pathways underlying these diseases are likely to help understand subsets of disease, identify responders to a specific treatment and develop better therapeutics for AID.
The FDA in the 21st Century Stockbridge, Norman, MD, PhD; Miller, Kristen, PharmD; Amur, Shashi, PhD ...
JACC. Heart failure,
2017, January 2017, 2017-01-00, Volume:
5, Issue:
1
Journal Article
The Biomarker Qualification Program was established at the Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA) to expedite the integration of promising biomarkers ...across multiple drug development programs. The first set of biomarkers qualified in 2008 consisted of seven nonclinical safety biomarkers for the detection of acute drug‐induced nephrotoxicity in rats, and included urinary kidney injury molecule‐1 (KIM‐1). This article discusses the use of KIM‐1 in drug development and research before and after CDER's qualification of KIM‐1. Use was determined by analyzing relevant documents identified by keyword searches using three databases: 1) an FDA internal database, Document Archiving, Reporting, and Regulatory Tracking System (DARRTS); 2) ClinicalTrials.gov; and 3) PubMed. The results indicate increased use of KIM‐1 as a biomarker for detection of kidney injury in drug development programs reviewed by CDER, as well as in research following qualification.
Thousands of biomarker tests are either available or under development for lung diseases. In many cases, adoption of these tests into clinical practice is outpacing the generation and evaluation of ...sufficient data to determine clinical utility and ability to improve health outcomes. There is a need for a systematically organized report that provides guidance on how to understand and evaluate use of biomarker tests for lung diseases.
We assembled a diverse group of clinicians and researchers from the American Thoracic Society and leaders from the National Heart, Lung, and Blood Institute with expertise in various aspects of precision medicine to review the current status of biomarker tests in lung diseases. Experts summarized existing biomarker tests that are available for lung cancer, pulmonary arterial hypertension, idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, sepsis, acute respiratory distress syndrome, cystic fibrosis, and other rare lung diseases. The group identified knowledge gaps that future research studies can address to efficiently translate biomarker tests into clinical practice, assess their cost-effectiveness, and ensure they apply to diverse, real-life populations.
We found that the status of biomarker tests in lung diseases is highly variable depending on the disease. Nevertheless, biomarker tests in lung diseases show great promise in improving clinical care. To efficiently translate biomarkers into tests used widely in clinical practice, researchers need to address specific clinical unmet needs, secure support for biomarker discovery efforts, conduct analytical and clinical validation studies, ensure tests have clinical utility, and facilitate appropriate adoption into routine clinical practice.
Although progress has been made toward implementation of precision medicine for lung diseases in clinical practice in certain settings, additional studies focused on addressing specific unmet clinical needs are required to evaluate the clinical utility of biomarkers; ensure their generalizability to diverse, real-life populations; and determine their cost-effectiveness.
The 2019 13
Workshop on Recent Issues in Bioanalysis (WRIB) took place in New Orleans, LA, USA on April 1-5, 2019 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical ...companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers, immunogenicity and gene therapy. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS, LBA cell-based/flow cytometry assays and qPCR approaches. This 2019 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2019 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers New Insights in Biomarker Assay Validation, Current & Effective Strategies for Critical Reagent Management, Flow Cytometry Validation in Drug Discovery & Development & CLSI H62, Interpretation of the 2019 FDA Immunogenicity Guidance and Gene Therapy Bioanalytical Challenges. Part 1 (Innovation in Small Molecules and Oligonucleotides & Mass Spectrometry Method Development Strategies for Large Molecule Bioanalysis) and Part 2 (Recommendations on the 2018 FDA BMV Guidance, 2019 ICH M10 BMV Draft Guideline and regulatory agencies' input on bioanalysis, biomarkers, immunogenicity and gene therapy) are published in volume 11 of
, issues 22 and 23 (2019), respectively.
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