Linguamatics, the leader in natural language processing (NLP)-based text mining, announced that the Federal Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) has licensed its 12E text mining platform as a discovery and decision support tool to supplement laboratory research efforts on drug safety.  The FDA will use the platform to review published literature and drug product labels to address key biomedical issues, including mechanisms of drug toxicity and disease processes.  In addition to document retrieval, the 12E platform can identify, extract, synthesize, and analyze relevant facts and relationships (e.g., between genes and diseases, drugs and side effects).  Customers include top tier commercial, academic, and governmental organizations, including 9 of the top 10 global pharmaceutical companies.  The 12E platform is available both as an in-house or cloud-based system.

Typical applications in pharmaceutical, biotechnology, and healthcare include:
•    Mapping gene-disease relationships and identifying potentially novel therapeutic targets
•    Biomarker discovery
•    Drug repurposing
•    Drug safety
•    Patent analysis
•    Clinical trial site selection and study design
•    Mining electronic medical records to improve prediction of health outcomes
•    Translational medicine
•    Competitive intelligence
•    Social media mining
•    Subjective data mining (sentiment analysis, key opinion mining)

SourcesBioSpace and Business Weekly

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PDUFA V: Risk – Benefit Emphasis New

Posted by cdavenport on Friday Jun 29, 2012 Under Drug Safety, FDA, Risk Management

What is new about PDUFA V?   Congress, the media, and the public have a history of boiling down the issue to whether drugs are safe or not safe.  In reality the issue is benefit versus risk.   In addition, this judgement needs to be aligned with that of the patients who take the medication.  Emphasis on this risk-benefit framework is a landmark difference in the pending PDUFA V legislation.

Source:  Nature

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New Hypersensitivity Screen for Drugs

Posted by cdavenport on Friday Jun 22, 2012 Under Drug Safety, Immunogenicity, Preclinical, toxicity, Toxicology

Many drug hypersensitivity reactions are HLA-linked, meaning that they will occur much more often or even exclusively in individuals who have certain variants of the HLA gene.  A new study elucidates the specific mechanism leading to HLA gene-linked hypersensitivity to the drug abacavir.  These findings are applicable to other drugs and related hypersensitivity reactions.

The findings are discussed in the paper “Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire,” published last week in the scientific journal Proceedings of the National Academy of Sciences.

An interview with the authors is published in the Source cited below.

Source:  Clinical Toxicology

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Drug Safety: Tip of the Iceberg

Posted by cdavenport on Thursday Jun 7, 2012 Under Drug Safety, FDA, Post-market Surveillance, Risk Management, toxicity

The 10 drugs with the largest numbers of reports sent directly to the FDA by healthcare practitioners and consumers in 2011 in order of frequency are Pradaxa, Coumadin, Levaquin, Carboplatin, Zestril, Cisplatin, Zocor, Cymbalta, Cipro and Bactrim.  It is interesting to note that just two of these drugs were first introduced in the last decade (Pradaxa and Cymbalta), and only one in the previous year (Pradaxa), suggesting that major drug safety issues are not confined to recently approved drugs.  On one hand, this shows that FDA and manufacturer safety surveillance programs have identified these significant safety risks. On the other, it illustrates that placing warnings in product information only begins the process of managing drug safety risks.   Relative rates vs. report expectations are detailed.

These data come from QuarterWatch™ an Institute for Safe Medication Practices surveillance program that monitors all serious and fatal adverse drug events (ADEs) reported to the Food and Drug Administration through MedWatch, its adverse event reporting system.  The goal is to identify signals that may represent important new drug safety issues.


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Nonclinical Cardiotoxicity Testing: Stem Cell Use

Posted by cdavenport on Thursday Oct 13, 2011 Under Cardiovascular, Drug Safety, Techniques

Prospective identification and potential amelioration of cardiotoxicity is a critical component of contemporary drug development, particularly for targeted therapies (e.g., tyrosine kinases) in oncology that are designed to inhibit critical signaling pathways shared by both the tumor cell and the cardiac myocyte (e.g., HER2 and C-Abl).  Current preclinical approaches to cardiac safety, which often focus primarily on ion channel testing (e.g., hERG), need to broaden the in vitro test menu to assess other cellular functions that are critical to cardiac cell health.  Accordingly, effective nonclinical cardiotoxicity screening programs need to be implemented earlier in the development process.

Stem-cell technologies offer induced pluripotent stem-cell-derived (iPSC) cardiac myocytes that are pure, functionally relevant (exhibit electrical profiles in culture and are amenable to patch-clamp-like studies that monitor electrical potentials and voltage-gated ion channel function), and are human in origin.  The following would comprise an effective preclinical cardiac safety testing program utilizing  iPSC-derived cardiac myocytes:

  • Determining influences on key cardiac metabolic pathways focusing on AMPK;
  • Evaluating changes in fatty acid beta-oxidation;
  • Measuring changes in mitochondrial health , reactive oxygen species production, and ATP levels;
  • Assessing drug-induced apoptosis;
  • Survey potential off-target effects using a comprehensive kinase profiling platform.

In addition to the above, the preclinical program should identify compounds that demonstrate cardio-protective effects with regard to mitochondrial health and energy homeostasis.


ABL1 = a proto-oncogene which encodes a cytoplasmic (C-ABl) and nuclear protein tyrosine kinase.  Implicated in processes of cell differentiation, cell division, cell adhesion, and stress response.

AMPK = a metabolic sensor of cellular ATP.  Controls fatty acid oxidation and glucose uptake in skeletal muscle, heart, and liver.

ATP = adenosine-5′-triphosphate, a multifunctional nucleoside triphosphate used in cells as a coenzyme.  Responsible for intracellular energy transfer.

HER2 = “Human Epidermal growth factor Receptor 2,” a receptor required for healthy heart function.

hERG = the human Ether-à-go-go Related Gene.  Codes for a potassium ion channel protein.


SourceDrug Discovery and Development

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Zebrafish: Preclinical Screening and Toxicity Assessment

Posted by cdavenport on Saturday Sep 3, 2011 Under Drug Safety, Techniques, Toxicology

Zebrafish offer a nonclinical model for the high-throughput screening of drug compounds, including toxicity assessment, with resolution at the cellular level in living vertebrate organisms.  These small, freshwater, tropical fish share genetic and biochemical similarity to humans, in addition to similar organ system development.  Vertebrate disease models (e.g., Parkinson’s, epilepsy, wound repair) are available , as are 3-D image resolution and data analysis capabilities.  Live-imaging options, unparalleled in other vertebrate organisms, are possible using the transparent larvae.  Furthermore, live-cell microscopy can provide views of the inner complexity and workings at the cellular level.  For purposes of disease modeling, researchers can create and screen genetic mutants in the zebrafish that are linked to human immune diseases.  Neurological assessments using the live, transparent, zebrafish larvae allow visualization of the mechanisms of myelination.  In conclusion, the zebrafish preclinical model owes much of its popularity to the transparent nature and relevant ease of imaging of vertebrate larvae.  Optimization of data analyses for these varied indications is ongoing.

Source:  Genetic Engineering and Biotechnology News

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Drug Labels: Toxicity or Information Overload?

Posted by cdavenport on Saturday May 28, 2011 Under Drug Safety, Risk Management, toxicity

Side effect overload on drug labels has less to do with true toxicity and drug safety than with manufacturer liability.  Examination of more than 5600 drug labels yielded over half a million side effects.  An average drug label and the more commonly prescribed drugs averaged 70 and 100 side effects, respectively.  The upper range in a single label was 525 reactions.  Information overload can overwhelm physicians, who must weigh the risks and benefits when prescribing a medication.  The Food and Drug Administration discourages such ‘over warning,’ but information overload is presently the rule rather than the exception.  Not surprisingly, medications typically used by psychiatrists and neurologists had the most complex labels, while drugs used by dermatologists and ophthalmologists had the least.  Although providing drug safety information more efficiently to both health care providers and the public is warranted, drug manufacturer liability concerns must also be addressed.

Source: Drug Discovery and Development

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Turbulent Blood Flow may Increase Cardiovascular Risk

Posted by cdavenport on Wednesday Feb 23, 2011 Under Cardiovascular, Drug Safety, toxicity

By utilizing the basic principles of hemodynamics and hydraulics, research suggests that fluid retention is detrimental for the cardiovascular system because it increases the likelihood of turbulent blood flow, regardless of whether or not blood pressure is raised.  Increased turbulence promotes endothelial dysfunction, thereby contributing to the development of atherosclerotic cardiovascular disease.  Fluid retention induces hypertension in some individuals, increases stroke volume (the amount of blood that is ejected by the heart with each contraction) in others, and causes edema.  Some blood pressure lowering medications also increase stroke volume and cause edema but prevent heart attacks and strokes when used to treat hypertension.  For drugs that increase the risk of adverse cardiovascular events, it may be possible to reduce or neutralize the increased risk by simultaneous diuretic administration.

Source: ScienceBlog

Original Article: Clinical Hemorheology and Microcirculation (free pdf)

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Drug Labels May Inadequately Address Efficacy and Risk

Posted by cdavenport on Thursday Nov 25, 2010 Under Drug Safety, FDA, toxicity

FDA approval does not mean that a drug works well; it means only that the Agency deemed its benefits to outweigh its harms.  Comparative efficacy data, other than to placebo, may be missing from the label.  In 2006, the FDA revised the drug label design, adding a “highlights” section to emphasize the drug’s indications and warnings.  It also issued guidance about reporting trial results in the label and emphasized the importance of effectiveness data.  Yet some recent label updates (e.g., for Lunesta and Rozerem) are substantively unchanged.  Use of “Prescription Drug Facts Boxes,” featuring a data table of benefits and toxicities has been proposed.  Recently, the FDA’s Risk Advisory Committee recommended that the FDA adopt these boxes as the standard for their communications.  FDA leadership is deciding whether and how to use the boxes in reviews, labels, or both.  Also proposed is the generation of a standardized executive summary of FDA drug reviews.  These summaries should include data tables of the main results of the phase 3 trials, highlight reviewers’ uncertainties, and note whether drug approval was conditional upon a post-approval study.  While publication of new comparative-effectiveness results is helpful, publications generally occur post approval.  In contrast, much is known about drug effectiveness and drug safety at approval that could better guide physician and patient choice if this information was more widely disseminated.

Source: New England Journal of Medicine

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Historical Overview

During the past 30 years, genetic toxicology testing has evolved technologically to play an important safety assessment role in the progression of chemical candidates through the drug discovery and development process.  Prior to application of the battery of regulatory tests, high-throughput screening assay methods are now used to reduce costs by terminating compounds with undesirable characteristics (mutagenic hazard or potential carcinogen).  With few exceptions, compounds found to be mutagenic in these assays are dropped from development, and clastogenic compounds result in unfavorable labeling, require disclosure in clinical trial consent forms, and can greatly impact the marketability of a new drug.  Furthermore, in vitro clastogenicity responses can delay drug development by requiring additional testing to determine the in vivo relevance, although these assays can at times be integrated into other in vivo toxicity studies to expedite the progression of drugs to clinical trials.  Thus, genetic toxicology testing at the drug discovery and optimization stages serves to quickly identify mutagenic compound so that they can be quickly dropped from development.

Genetic toxicology was the first branch of toxicology to fully embrace in vitro test methods, notably through the visionary work of Bruce Ames and coworkers with the development of the Salmonella typhimurium tester strains.  These prokaryotic assays demonstrated good correlation with rodent carcinogenicity results.  The Ames test is generally used as the first screening method to assess chemical genotoxicity.   Although it provides extensive information on DNA reactivity, the Ames assay is not suitable for detecting nongenotoxic carcinogens.  In time, in vitro assays were developed for the detection of gene mutations, chromosomal aberrations, and micronuclei formation.  The mouse lymphoma assay in particular has been developed to the point that  both gene mutations and chromosomal aberrations can be detected and quantified following exposure to test chemicals, when compared with known direct-acting mutagens and promutagens.

Current Perspectives

Assay Predictivity

The performance of a combination of the 3 most commonly used in vitro genotoxicty tests – the Ames, the mouse lymphoma, and the in vitro micronucleus or chromosomal aberration tests – have been evaluated for their ability to discriminate rodent carcinogens from non-carcinogens using a database of over 700 chemicals (Kirkland et al., 2005).  Based on the relative predictivity  measure (RP; the ratio of real:false positive results), that study demonstrated that positive results in all 3 tests indicated that a chemical is greater than 3 times more likely to be a rodent carcinogen than a non-carcinogen.  Similarly, negative results in all three tests indicated that a chemical is more than two times more likely to be a rodent non-carcinogen than a carcinogen.  But further evaluation of combinations of positive and negative results in this genotoxicity battery using the RP calculations indicated that it is not possible to predict outcome of a rodent carcinogenicity study when only 2/3 of the genotoxicity results are in agreement (Kirkland et al., 2006).

Assay Shortcomings

A basic if not critical shortcoming in all these mammalian in vitro assays is the lack of mammalian absorption, distribution, metabolism, and excretion (ADME) features.  As summarized in a recent European Centre for the Validation of Alternative Methods (ECVAM) workshop (Kirkland et al., 2007), cell lines used for genotoxicity testing have a number of deficiencies that may contribute to a high false-positive rate.  These include a lack of normal metabolism leading to reliance on exogenous metabolic activation systems (e.g., Aroclor-induced S9), impaired tumor protein 53 (p53) transcription factor function, and altered deoxyribonucleic acid (DNA) repair capacity.  Also the use of excessive test chemical concentrations to achieve an empirical correlation between genotoxicity and carcinogenicity can result in “promiscuous activation.”  Because these in vitro assays rely on such artificial activation systems, other enzymes that are relatively unimportant in vivo may take over the activation role, leading to the same or a different metabolite – hence, “promiscuous activation.”  Recently, a risk assessment method has been proposed that is dependent upon the availability of quantitative human and rodent ADME  data such that exposures to a metabolite of genotoxic concern can be estimated at the intended human efficacious dose and the maximum dose used in the 2-year rodent bioassay (Dobo et al., 2009).

Other notable genotoxicity testing methods are available for use in the drug discovery and lead-optimization process.  The comet assay is a microgel electrophoresis technique for detecting DNA damage – in vitro and in vivo- at the level of a single cell.  When used in vivo, DNA lesions can be measured in any organ, regardless of the extent of mitotic activity and under normal ADME conditions.  The conventional mouse micronucleus test in the hematopoietic system is a simple method to assess the in vivo clastogenicity of chemicals if the chemical reaches the hematopoietic system.  When multiple organs in the mouse were analyzed following exposure to 208 chemicals, the comparison of comet assay results and carcinogenicity suggested that the comet assay was more capable than the mouse micronucleus assay of detecting rodent carcinogens (Sasaki et al., 2000).

Regulatory Guidance

At present, the ICH/FDA Guidance Document S2(R1) outlines two GLP genotoxicity testing assay options.  Option 1 requires completion of: (1) a test for gene mutation in bacteria., (2) a cytogenetic test for chromosomal damage (choice of three), and (3) an in vivo test for chromosome damage using rodent hematopoietic cells (either micronuclei or chromosomal aberrations in metaphase cells).  Option 2 combines (1) the highly predictive gene mutation assay in bacteria with (2) an in vivo assessment in 2 tissues (e.g., micronuclei using rodent hematopoietic cells plus a second in vivo assay, such as the liver unscheduled DNA synthesis (UDS) assay, transgenic mouse assay, comet assay, etc.  Thus, the ICH guidance allows  for the registration of pharmaceuticals without the submission of data from in vitro mammalian genotoxicity tests (e.g., the in vitro micronucleus test, chromosomal aberrations, mouse lymphoma assay).  This is important because some authors (Matthews et al., 2006) have indicated that 2 of the tests in the FDA battery show good correlation for carcinogenicity prediction (Ames and in vivo micronucleus) and 2 tests show poor correlation (mouse lymphoma and in vitro chromosomal aberrations).

High-Throughput Screens

With the trend towards the application of early pre-screening, high-throughput methods to eliminate potential mutagens/clastogens prior to application of the more resource-intensive and time-consuming regulatory testing methods, many pharmaceutical companies are using these screening methods early in the discovery/lead optimization process.  Examples of modified or high-throughput methods for early screening include: (1) computer-assisted (in silico) structural activity relationship (SAR) methods for predictive toxicity screening, (2) modified assays such as the in vitro assessment of micronucleus induction in Chinese hamster ovary (CHO) cells, the Ames II assay (TA98 and TA Mix), the in vitro comet assay, or well-based (e.g., 96- or 384-well format) modifications of the yeast deletion (DEL) assay, or (3) proprietary assays such as Vitotox™ (mutagenicity), RadarScreen® (clastogenicity), and GreenScreen® HC (genotoxicity).

About the Author:

David Amacher is a senior investigative and biochemical toxicologist with extensive experience in the safety evaluation of human and animal health products.  Dr. Amacher is a Diplomate of the American Board of Toxicology, a Fellow of the National Academy of Clinical Biochemistry, and serves as an Assistant Research Professor of Toxicology and Adjunct Professor in the Graduate School of the University of Connecticut.  His professional affiliations include memberships in the American Society for Pharmacology and Experimental Therapeutics, Society of Toxicology, American Society of Biochemistry and Molecular Biology, International Society for the Study of Xenobiotics, American Association of Clinical Chemistry, and the American College of Toxicology.


Dobo KL, Obach RS, Luffer-Atlas D, et al.  A strategy for the risk assessment of human genotoxic metabolites.  Chem Res Toxicol. 2009;22(2):348-56.

International Conference for Harmonization Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use.  S2(R1), 6 March 2008.

Kirkland D, Aardema M, Henderson L, et al.  Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens: I. Sensitivity, specificity and relative predictivity [published erratum appears in Mutation Research 2005;588(1):70].

Kirkland D; Aardema M; Müller L; et al.  Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens II. Further analysis of mammalian cell results, relative predictivity and tumour profiles.  Mutation Research 2006;608(1):29-42.

Kirkland D; Pfuhler S; Tweats D; et al.  How to reduce false positive results when undertaking in vitro genotoxicity testing and thus avoid unnecessary follow-up animal tests: Report of an ECVAM Workshop.  Mutation Research 2007;628(1):31-55.

Matthews EJ, Kruhlak NL, Cimino MC, et al.  An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: I.  Identification of carcinogens using surrogate endpoints.  Regul. Toxicol. Pharmacol. 2006;44(2):83-96.

Sasaki YF, Sekihashi K, Izumiyama F., et al.  The comet assay with multiple mouse organs: comparison of comet assay results and carcinogenicity with 208 chemicals selected from the IARC Monographs and U.S. NTP Carcinogenicity Database.  CRC Crit. Rev. Toxicol. 2000;30(6):629-799.

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