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Post-Approval Drug Safety Strategies  November 8-9, 2010 • Philadelphia, PA Program | Register | Download Brochure   
Improving products’ clinical safety will increase the industry’s fundamental value proposition to patients, healthcare providers, payors and regulators. Pressing issues executives are facing today include Optimizing the allocation of an organization's drug safety assessment, evaluation and minimization resources and costs, Integrating drug safety knowledge longitudinally across a compound's lifecycle; practical approaches to Lifecycle Signal Detection and How to negotiate with regulators to avoid costly and, in some cases, unnecessary, risk management plans.  Post-Approval Drug Safety Strategies conference Nov. 2010

adverse drug event ADE:  Recently, another more inclusive term, Adverse Drug Event (ADE) has come into use. According to Bates et al, the term ADE, defined as an injury resulting from medical intervention related to a drug, is preferred since it is more comprehensive and clinically significant than the ADR. (JAMA 1995;274:29- 34). [Saeed A Khan, "Drug Interaction or Adverse Drug Reaction? Confusing Terms", British Medical Journal 10 July, 1998] http://bmj.com/cgi/eletters/316/7149/1930

Google = about 2,420 May 8, 2003; about 83,700 Nov 10, 2006, about 59,600 Oct. 28, 2008, about 69,000 May 14, 2009

Related terms: adverse drug reaction ADR, drug interaction 

adverse drug reaction ADR:  ADRs may include drug interactions as one of many causes but the reverse is not true. The reader is cautioned regarding usage of drug reaction terms as multiple nearly- similar terms of varying granularity abound. .. "An adverse reaction to a drug has been defined as any noxious or unintended reaction to a drug that is administered in standard doses by the proper route for the purpose of prophylaxis, diagnosis, or treatment(2). However, WHO's original definition of ADR excluded therapeutic failures, intentional and accidental poisoning and drug abuse, as well as adverse events due to medication errors such as drug administration or non- compliance(1) ... Due to non- uniform usage of these terms, it is sometimes difficult to compare various studies and derive incidence rates, etc. for ADRs, and Drug Interactions. Saeed A Khan, "Drug Interaction or Adverse Drug Reaction? Confusing Terms", British Medical Journal 10 July, 1998 http://bmj.com/cgi/eletters/316/7149/1930

We define an adverse drug reaction as "an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product." Such reactions are currently reported by use of WHO's Adverse Reaction Terminology, which will eventually become a subset of the International Classification of Diseases. Adverse drug reactions are classified into six types (with mnemonics): dose-related (Augmented), non-dose-related (Bizarre), dose-related and time-related (Chronic), time-related (Delayed), withdrawal (End of use), and failure of therapy (Failure).  Edwards, IR; Aronson JK,  Adverse Drug Reactions, Definitions, Diagnosis and Management, Lancet 356(9237): 1255- 1259, 2000 Oct 7

Google = about 14,500 May 8, 2003; about 475 Nov 10, 2006, about 560,000 Oct. 28, 2008, about 1,400,000 May 14, 2009

WHO, Adverse Reaction Terminology, 2009 http://www.umc-products.com/graphics/3036.pdf 
Wikipedia http://en.wikipedia.org/wiki/Adverse_drug_reaction 

Related terms: adverse drug event ADE, drug interaction 

animal models and drug safety: Improving predictability through novel approaches. Sessions include improving current models, New studies in carcinogenicity testing: better work with rodents; Zebrafish and other alternative models; Failing early: Novel approaches for better predictability. Expanding impact of new animal models in drug safety June 2009 Philadelphia PA

antedrugs: The  antedrug concept was introduced by Lee and Soliman in 1982 in designing potent, yet safer locally active anti-inflammatory steroids. Antedrug  is defined as an active synthetic derivative that is designed to undergo biotransformation to the readily excretable inactive form upon entry in the systemic circulation, thus  minimizing systemic side effects and increasing the therapeutic indices  MO Khan et al   Antedrugs: an approach to safer drugs, Current Med Chem 2005;12(19): 2227-2239

Bayesian clinical forecasting: Clinical trials

biochemical toxicology: Of particular interest [to the Journal of Biochemical and Molecular toxicology] are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology. Journal of Biochemical and Molecular Toxicology, Wiley Periodicals http://www3.interscience.wiley.com/cgi-bin/jabout/38998/ProductInformation.html 
cardiotoxicity: Monitoring Cardiotoxicity and Drug Safety June 15-16, 2010 • Philadelphia, PA Program | Register

At least 50 companies have a claimed product or service relevant to cardiotoxicity screening, of which 29 have some clear focus on proarrhythmic cardiotoxicity or ion channel screening. ... Ion currents across a cardiac myocyte cell membrane cause a sequence of voltage changes known as the action potential, which is the basis of the heartbeat.  Drug-mediated interference with one or more of the ion channels that give rise to the action potential may cause potentially lethal arrhythmias. This could be brought about by direct binding of drug to ion channel proteins, or by indirect interference with ion channel function. The clinical outcome of drug-ion channel interactions could be potentiated by a variety of predisposing factors, such as concurrent disease, medication, genetic variations, age, and gender. Insight Pharma Reports, Cardiotoxicity issues, technologies and solutions for the future, 2008 

Cardiotoxicity is one of the major forms of toxicity seen in drugs and it accounts for most drug recalls and delays experienced in regulatory approvals. While improvements in experimental and clinical trial design have helped with better detection of cardiac toxicity in drug candidates, the problem still persists and often goes unnoticed until the compound is further along in development or has reached the market. 

computational toxicology: EPA’s Computational Toxicology Research Program is intended to provide innovative solutions to a number of persistent and pervasive issues facing EPAs regulatory programs. The vision of the program is an EPA that efficiently characterizes exposure, hazard, and risk through the broad use of modern biological tools, information technologies, and computational models. National Center for Computational Toxicology, US EPA, 2008  http://www.epa.gov/ncct/comptoxfactsheet.html 

disproportionate drug metabolite: A metabolite present only in humans or present at higher plasma concentrations in humans than in the animals used in Nonclinical studies. In general, these metabolites are of interest if they account for plasma levels greater than 10 percent of parent systemic exposure, measured as area under the curve (AUC) at steady. state  Glossary, Guidance for Industry, Safety testing of drug metabolites, FDA, 2008 http://www.fda.gov/CDER/GUIDANCE/6897fnl.pdf  

drug interactions: Molecular Medicine

drug metabolites: Guidance for Industry, Safety testing of drug metabolites, FDA, 2008 http://www.fda.gov/CDER/GUIDANCE/6897fnl.pdf  

drug safety: "No matter how good the science is," [Sanket] Agrawal [of Relsys]  says, "when a drug is released we can see only a percentage of the risks. If we want to know everything, it means we would never release a drug." The message should be that "all drugs are chemicals and come with side effects, known and unknown. Pharmaceutical companies need to communicate the benefits [correlated to price] versus the risks...and let people make informed decisions."  New Directions in Drug Safety, BioIT World, eCliniqua, Feb 2007    http://www.bio-itworld.com/archive/eclinica/index_02262007.htm 

CDER [FDA] evaluates the safety profiles of drugs available to American consumers using a variety of tools and disciplines throughout the life cycle of the drugs. We maintain a system of post marketing surveillance and risk assessment programs to identify adverse events that did not appear during the drug development process. We learn about adverse events through required reporting by companies and through voluntary reports submitted to FDA’s MedWatch program, which together total more than 250,000 reports per year. Staff in the Office of Drug Safety use this information to identify drug safety concerns and recommend actions to improve product safety and protect the public health.  Activities include updating drug labeling, providing more information to the community, implementing or revising a risk management program, and, on rare occasions, reevaluating approval or marketing decisions. Office of Drug Safety, CDER, FDA  http://www.fda.gov/cder/Offices/ODS/default.htm 

Improving products’ effective clinical safety will increase the industry’s fundamental value proposition to patients, healthcare providers, payors and regulators. The program will focus on pharmacovigilance program implementation and specific strategies and approaches to creating true value from a peri- and post-approval drug safety program. Drug safety programs and monitoring and the approach of this conference are not to look at safety in the silos of early-phase safety or post-approval safety but to view safety holistically, across the lifecycle, especially at the transition from approval to broader use in the marketplace. 

Narrower terms: pharmacovigilance, Phase IV, post approval drug safety, preclinical drug safety

Drug Safety Executive Council:  A peer-to-peer membership of over 1,600 drug safety leaders with the common objective of advancing the development of better and safer medicines. http://www.drugsafetycouncil.org/  

Drug Safety Initiative,  FDA http://www.fda.gov/cder/drugSafety.htm  

EMEA: European Agency for the Evaluation of Medicinal Products http://www.emea.eu.

ecotoxicogenomics: Understanding the biological effects of exposures to chemicals in the environment relies on classical methods and emerging technologies in the areas of genomics, proteomics, and metabonomics. Linkages between the historical and newer toxicological tools are currently being developed in order to predict and assess risk. Being able to classify chemicals and other stressors based on effects they have at the molecular, tissue, and organismal levels helps define a systems biology approach to development of streamlined, cost-effective, and comprehensive testing approaches for evaluating environmental hazards. AL Miracle, GT Ankley, Ecotoxicogenomics: linkages between exposure and effects in assessing risks of aquatic contaminants to fish. Reprod Toxicol 19(3): 321- 326, Jan- Feb 2005 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15686867&query_hl=23

Google = about 275 Nov. 5, 2005; about 511 Nov. 17, 2006, about 2,810 Oct 28, 2008

ecotoxicology:  To facilitate the application of chemistry in ecotoxicology, there is a need for a glossary addressing the terms in ecotoxicology essential for communication between the disciplines. This project will create such a glossary, reflecting IUPAC's concern about the impact of chemicals on health and the environment. It will also complement the previous projects which resulted in glossaries in toxicology and toxicokinetics. IUPAC, Glossary of terms used in ecotoxicology http://www.iupac.org/projects/2005/2005-047-1-700.html 

Wikipedia http://en.wikipedia.org/wiki/Ecotoxicology 

Google = about 2,210,000 Nov 17, 2006, about 1,210,000 Oct. 28, 2008 

ED 50:  Abbreviation for median effective dose. 

evidence- based toxicology: Evidence-based toxicology: a comprehensive framework for causation, Guzelian PS, Victoroff MS, Halmes NC, James RC, Guzelian CP., Hum Exp Toxicol. 2005 Apr;24(4): 161-201 

FDA: Every day the Food and Drug Administration (FDA) works to balance expeditious access to drugs with concerns for safety, consonant with its mission to protect and advance the public health. The task is all the more complex given the vast diversity of patients and how they respond to drugs, the conditions being treated, and the range of pharmaceutical products and supplements patients use. Reviewers in the Center for Drug Evaluation and Research (CDER) at the FDA must weigh the information available about a drug’s risk and benefit, make decisions in the context of scientific uncertainty, and integrate emerging information bearing on a drug’s risk-benefit profile throughout the lifecycle of a drug, from drug discovery to the end of its useful life. These processes may have life-or-death consequences for individual patients, and for drugs that are widely used, they may also affect entire segments of the population.  Future of Drug Safety: Promoting and Protecting the Health of the Public, National Academies Press, 2007 http://books.nap.edu/openbook.php?record_id=11750&page=1 

good pharmacovigilance practice: 
hepatotoxicity:  Early Assessments for Predicting Hepatotoxicity June 16-17, 2010 • Philadelphia, PA Program | Register |

Hepatotoxicity is the number one cause for drug recalls and new drug refusals based on adverse drug reactions. According to FDA and industry sources hepatotoxicity accounts for ~27% of the drugs withdrawn from the market since 1960 and is responsible for greater than 40% of the clinical phase drug candidate terminations. 

Wikipedia http://en.wikipedia.org/wiki/Hepatotoxicity   

idiosyncratic toxicity: The primary role of Phase IV post marketing surveillance is to detect rare or idiosyncratic adverse events that do not manifest in the population sizes common to clinical trials ... While clinical forecasting is aimed at predicting safety and efficacy early in the drug development process, rare or idiosyncratic toxicities can only be detected in Phase IV.  There, Phase IV serves as a very important safety net, to catch problems that could not be predicted.  Insight Pharma Reports, Bayesian Forecasting of Phase III Outcomes: The Next Wave in Predictive Tools, June 2007   

Few drug development surprises can be as devastating as toxicity problems that only show up under a combination of conditions as idiosyncratic toxicity. Because of the role of variations in human drug metabolizing enzymes there may only be subtle (or no) evidence of such problems during pre-clinical safety studies. Such problems are also unlikely to show up in all but the largest clinical trials, but if the side effects are serious, it can result in product withdrawal.   

immunogenicity: 
Immunogenicity Summit   October 19-21, 2010 • Philadelphia, PA  Program | Register | Download Brochure  

immunotoxicology: Immunotoxicology of both organic and inorganic substances is presently of great interest in occupational and environmental health  ... In preparing the immunochemical papers, it became clear that there is a large number of specialized terminology foreign to chemists and not included in the Glossary of Terms Used in Toxicology (2nd ed.). In addition, a number of terms are somewhat ambiguous even within the discipline of immunology, and their precise definition will help to clarify regulatory and legislative discussion. We believe that this will add significantly to the value of the Immunosensitization project, as well as being an essential addition to the toxicology glossaries referred to above.  IUPAC Glossary of terms used in immunotoxicology project, 2008   http://www.iupac.org/web/ins/2007-053-1-700 

in vitro adventitious assay: Assays & screening

ion channel assays for drug safety: Ion channels are involved in a complex and intricate signaling system that play an important role in affecting the cellular response to a drug, and hence, to the overall patient safety. Drug-induced alterations in the translation and trafficking of ion channel proteins and drug-induced blockade of channels are all thought to contribute to drug-related adverse events. In vitro assays using isolated cells, cell lines, and expression systems cloned for specific ion channels are now routinely used, alongside electrophysiology experiments, to identify potential drug liabilities. This course provides a detailed overview of the types of ion channel-based screening assays and technologies that are currently in use and how they are being applied to effectively monitor and predict drug safety. Ion channel assays for drug safety short course: World Pharma Congress June 2009 Philadelphia PA

LD 50:  The dose of a substance that will kill half (50%) of the treated test animals when given as a single dose.  A measure of acute toxicity. Chemical Hygiene Glossary of Terms, Environment, Health & Safety Lab, Lawrence Berkeley National Laboratory, US

metabolite: A compound derived from the parent drug through Phase I and/or Phase II metabolic pathways, Glossary,  Guidance for Industry, Safety testing of drug metabolites, FDA, 2008 http://www.fda.gov/CDER/GUIDANCE/6897fnl.pdf   

Any intermediate or product resulting from metabolism. IUPAC  International Union of Pure and Applied Chemistry, Glossary for Chemists of terms used in biotechnology. Recommendations, Pure & Applied Chemistry 64 (1): 143-168, 1992

See also Metabolic Profiling

molecular pharmacology: Pharmacogenomics

molecular toxicology:  The scope [of the Journal of Biochemical and Molecular Toxicology] includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, activation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology. Journal of Biochemical and Molecular Toxicology, Wiley Periodicals http://www3.interscience.wiley.com/cgi-bin/jabout/38998/ProductInformation.html 

nanotoxicology: Results of older biokinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. G. Oberdorster, J. Oberdorster, E. Oberdorster, Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles, Environmnental Health Perspectives, 113 (7) : 823- 839, July 2005 

Wikipedia http://en.wikipedia.org/wiki/Nanotoxicology 

Google = about 29,200 Dec. 13, 2005, about 27, 700 Dec 26, 2007, about  53,100  Oct. 24, 2008
nephrotoxicity: New Tools for Detecting Nephrotoxicity  June 15-16, 2010 • Philadelphia, PA Program | Register | 

Patient Reported Outcomes Consortium: Clinical trials & Drug approvals

pharmacoepidemiology: The study of the utilization and effects of drugs in large numbers of people. To accomplish this study, pharmacoepidemiology borrows from both pharmacology and epidemiology. About Pharmacoepidemiology, International Society Pharmacoepidemiology, 2004 http://www.pharmacoepi.org/aboutpe.cfm 

pharmacological biomarkers: Biomarkers

pharmacologically active metabolite: A metabolite that has pharmacological activity at the target receptor. The activity may be greater than, equal to, or less than that of the patent drug. Glossary,  Guidance for Industry, Safety testing of drug metabolites, FDA, 2008 http://www.fda.gov/CDER/GUIDANCE/6897fnl.pdf   

pharmacovigilance: The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems. The Importance of Pharmacovigilance, WHO 2002  http://www.who-umc.org/defs.html#pvr  

The process of (a) monitoring medicines as used in everyday practice to identify previously unrecognised or changes in the patterns of their adverse effects; (b) assessing the risks and benefits of medicines in order to determine what action, if any, is necessary to improve their safe use; (c) providing information to users to optimise safe and effective use of medicines; (d) monitoring the impact of any action taken.  Medicines Control Agency, UK, Pilot publication scheme, Glossary of terms, 2003 http://www.mca.gov.uk/pilot/app1.htm#A

Related term: post marketing surveillance  Broader term: drug safety

Phase IV/ postmarketing surveillance: At this stage, after a drug has been launched, pharmaceutical companies may conduct further studies of its performance, often examining long- term safety.  See also clinical trials, phase I, II, III

post approval drug safety: 
Post-Approval Drug Safety Strategies  November 8-9, 2010 • Philadelphia, PA Program | Register | Download Brochure

A new study from Duke University and The University of North Carolina at Chapel Hill estimates that in 2003 the top 20 pharmaceutical manufacturers spent a total of $800 million, or 0.3 percent of sales, on drug safety monitoring following FDA approval. In the same year, pharmaceutical companies spent 15.6 percent of sales on research and development of new drugs. Study examines Pharmaceutical Spending on Post Approval drug safety, Duke University News & Information, 2007   http://www.fuqua.duke.edu/news/faculty/ridley-spending-0306.html 

Broader term: drug safety  Related term: pharmacovigilance

post marketing surveillance: See Phase IV Post Marketing Surveillance

preclinical drug safety: 

predictive ADME: The completion of the Human Genome Project and recent advances in our understanding of the molecular mechanisms of diseases have provided increasing numbers of newly defined biological pathways and networks with potential preventive or therapeutic targets. The development of molecular diversity libraries and screening of these libraries have provided tremendous opportunities to discover new chemical and biological agents for the prevention and treatment of diseases. This created the belief that increasing numbers of new molecular entities would enter clinical testing and would receive approval from the Food and Drug Administration (FDA) to treat human disorders. However, this has not occurred. Many candidate agents are failing during clinical testing because of their unfavorable pharmacokinetic properties, unacceptable adverse effects, or major toxicities, as well as the lack of efficacy.

The safety of each new chemical entity must be demonstrated prior to its entry into clinical trials. Investigational New Drug (IND) applications to the FDA require chemistry, manufacturing, and control information and results from preclinical toxicology studies for the safety of new agents. Results of nonclinical pharmacokinetic studies for defining ADME properties, addressing important safety issues, or assisting the evaluation of toxicology data for investigational new agents are highly desirable in IND submissions. Novel preclinical tools for Predictive ADME-Toxicology RFA Number: RFA-RM-04-023, 2004   http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-04-023.html#PartI 

predictive safety: Unexpected toxicity is the single greatest cause of pipeline attrition. Despite the fact that a typical preclinical safety program will consume about 1,300 rats and 90 dogs, there is no guarantee that the compound will not present safety problems serious enough to warrant termination. Insight Pharma Report  Outlook for Predictive Safety Technologies, 2006

Predictive Safety Testing Consortium: http://www.fda.gov/oc/initiatives/criticalpath/projectsummary/consortium.html  See also Biomarkers

predictive toxicogenomics: A number of novel approaches to toxicology research that have become available over the past five years that are raising optimism for dramatic improvements in the field. Strategic regulatory, and marketplace issues are driving growth of toxicogenomic and predictive toxicology applications. The ability to predict the toxic effects of potential new drugs is crucial to prioritizing compound pipelines and eliminating costly failures in drug development. The inability to accurately predict toxicity early in drug development cost the pharmaceutical industry $8 billion in 2003, approximately one-third the cost of all drug failures. Even when drugs successfully obtain FDA approval and reach the market, they remain vulnerable to costly safety issues.  

predictive toxicology: An in-depth survey of strategies to characterize chemical structures and biological systems-covering prediction methods and algorithms, sources of high-quality toxicity data, the most important commercial and noncommercial predictive toxicology programs, and advanced technologies in computational chemistry and biology, statistics, and data mining. Predictive Toxicology The Book, CRC Press, 2005 http://www.predictive-toxicology.org/ 

PSURs Periodic Safety Update Report: Designed to be a stand- alone document that allows a periodic but comprehensive assessment of the worldwide safety data of a marketed drug or biological product. MJ Klepper, The periodic safety update report as a pharmacovigilance tool, Drug Safety 27(8): 569- 578, 2004

REMS Risk Evaluation and Mitigation Strategy : The Food and Drug Administration Amendments Act of 2007 gave FDA the authority to require a Risk Evaluation and Mitigation Strategy (REMS) from manufacturers to ensure that the benefits of a drug or biological product outweigh its risks.  Approved Risk Evaluation and Mitigation Strategies , 2010 http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm

risk: November 8-9, 2010
Mitigating Safety Risks in Early Clinical Development: Bridging the Gap between Preclinical and Clinical Safety to Improve Prediction
Philadelphia, PA

safety pharmacology: Pharmacology studies can be divided into three categories: primary pharmacodynamic, secondary pharmacodynamic, and safety pharmacology studies. For the purpose of this document, safety pharmacology studies are defined as those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above. ICH Guidance for Industry, S7A Safety Pharmacology Studies for Human Pharmaceuticals,  2001 http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129156.pdf 

a distinct scientific discipline that integrates the best practices of pharmacology, physiology and toxicology. The objective of Safety Pharmacology studies is to further the discovery, development and safe use of biologically active chemical entities by the identification, monitoring and characterization of potentially undesirable pharmacodynamic activities in nonclinical studies.  Mission Statement, Safety Pharmacology Society http://www.safetypharmacology.org/mission.asp 

Safety Surveillance Research Program:  Safety surveillance of new drugs is a critically important element of the drug development process. Safety surveillance is designed to detect adverse drug events for new products on the market, thereby limiting exposure of patients to the hazards of new medications. Safety surveillance has come under intense scrutiny due to high-profile lapses in effective detection that reveal the inadequacies of the system, which include Voluntary reporting system that is estimated to capture only 1 to 10% of adverse events, System is not ideal for distinguishing between adverse events caused by a drug and adverse events caused by the underlying condition for which the drug is indicated,  Product withdrawals lead to increased costs due to product liability and potential loss of efficacious treatments. Center for Biomedical Innovation, MIT, US http://web.mit.edu/cbi/research/SafetySurveillance.html  

Sentinel Initiative: On May 22, 2008, FDA launched the Sentinel Initiative with the ultimate goal of creating and implementing the Sentinel System--a national, integrated, electronic system for monitoring medical product safety. The Sentinel System will enable FDA to query multiple, existing data sources, such as electronic health record systems and medical claims databases, for information about medical products. The system will enable FDA to query data sources at remote locations, consistent with strong privacy and security safeguards.  Data sources will continue to be maintained by their owners.  This historic new system will strengthen FDA's ability to monitor the performance of a product throughout its entire life cycle. FDA, US http://www.fda.gov/oc/initiatives/advance/sentinel/ 

side- effect: The old term "side effect" has been used in various ways in the past, usually to describe negative (unfavourable) effects, but also positive (favourable) effects. It is recommended that this term no longer be used and particularly should not be regarded as synonymous with adverse event or adverse reaction. ICH Topic E 2 A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, EMEA European Agency for the Evaluation of Medicinal Products CPMP/ICH/377/95, 1994 http://www.emea.eu.int/pdfs/human/ich/037795en.pdf

Related terms: ADE adverse drug effect, ADR adverse drug reaction

susceptibility: This large diversity in responsiveness among individuals to environmental toxicants makes it difficult to determine actual risks, particularly at the low doses to which most people are exposed. Opportunities now exist for studies of genetic susceptibility for cancer and other diseases in which an environmental component can be presumed. Knowledge from such studies could, in the future, allow markers of genetic susceptibility to be incorporated into epidemiologic studies. This, in turn, would permit adjustment of  interpretation of results to account for genetic susceptibility, thus greatly enhancing the sensitivity and power of these studies to detect environmental components of important diseases. Other projects being considered are a nutrition initiative to determine how nutritional status alters disease susceptibility, and development of transgenic mice that carry important environmental response gene. NIEHS Strategic Plan 2000 "Individual susceptibility", National Institute of Environmental Health Sciences, US, March 2000 http://www.niehs.nih.gov/external/plan2000/suscptblty.htm

Susceptibility seems essentially synonymous with predisposition. Are there differences? 

Related terms: toxicogenomics, Molecular diagnostics & genetic testing genetic screening, predisposition test, predictive test, risk communication

systems pharmacology: Pharmacogenomics

systems toxicology: the combination of traditional toxicology methods with new strategies and tools for integrating high-throughput transcriptomics, proteomics, and metabolomics data. The goal is to better understand and predict potential toxicities at an early stage of drug development, so that biopharmas can gain deeper insights into the biology underlying toxicity, and make “go/ no-go” decisions well before committing to further development and clinical trials.  Kurt Zingler, Cross-Omics and Systems Toxicology, BioIT World 6 (9):  25,  Nov 2007  http://www.bio-itworld.com/issues/2007/nov/cross-omics-and-systems-toxicology/  

BEH.201 deals with the chemical and biological analysis of the metabolism and distribution of drugs, toxins and chemicals in animals and humans. The subject focuses on the mechanisms by which drugs and toxins cause therapeutic and toxic responses, as well as the use of metabolism and toxicity as a basis for drug development. MIT Graduate Studies in Applied Biosciences, Biological Engineering Fall 2003  http://stellar.mit.edu/S/course/BE/fa03/be.201/index.html 

Related terms: -Omes & -omics  cross-omics

therapeutic index TI:  The ratio of the LD50 to the effective dose (ED50). How close is the dose which will kill 50% of the tested animals to the dose required for the desired effect in humans? If these two doses are very close to each other, then there is an obvious danger in using the drug with humans. [US Dept. of Justice in the matter of MDMA Scheduling, Docket No. 84- 48, 1986 www.streetdrugs.org] http://www.mninter.net/~publish/mdma.htm

Related terms: ED 50, LD 50 Lethal Dose 50.

tox-chips: Developed at NIEHS [National Institute for Environmental Health Sciences, US], which contains copies, or clones, of about 2,000 of the 80,000 genes in the human body. Millions of  cloned copies of each gene form a nearly invisible dot that is "arrayed" - hence the name - in a grid pattern on the glass slide. The [NIEHS Microarray] center [at Research Triangle Park, NC] also uses an even newer microarray, called the Human ToxChip, containing clusters of each of  12,000 different cloned genes.

Toxic substances produce changes that express, or turn on and off, genes, the center  scientists said, and the chips and the accompanying computer support used to read the slides, take advantage of that linkage.  Initially the new center is evaluating known toxins - for example, chemicals that are known to cause cancer and/or mutations - to build a library or database showing the typical genetic changes that these known poisons produce. Once they have "signature" profiles of how known toxins change genes, the scientists said, they can evaluate other chemicals for potential harm by comparing the gene changes they produce with those made by the known toxins.  NIEHS "Environmental Health Institute to Use Gene Chips to Evaluate Chemicals for Potential Harm to Humans" Feb. 29, 2001  http://www.niehs.nih.gov/oc/news/toxchip.htm

Related terms: Microarrays

toxicity biomarkers:  The rising costs of drug development are putting pressure on pharmaceutical companies to reduce clinical attrition and maximize decision-making at the preclinical stage. One of the keys to reducing the cost and time of drug development is early and accurate safety evaluation of candidate drugs. The growing understanding of the toxicity mechanisms is creating an opportunity to develop toxicity biomarkers at the preclinical, clinical, and post-market stages. .  Toxicity Biomarkers: Optimizing Early Safety Assessment to reduce attrition, Sept. 17-19, 2007, Philadelphia PA  

Google about 407 Oct. 25, 2004; about 613 Oct. 11, 2005, about 714 Nov 14, 2006; about 9,290 April 6, 2007

Google = "toxicity markers" about  205 Aug. 6, 2002; about 186 Aug. 18, 2003; about 294 Sept 2, 2004, about 590 Nov 14, 2006,l about 757 Apr 6, 2007

toxicity testing: An important part of the drug- lead- optimization process in which investigational compounds are tested for their potential to cause side effects. CHA, Cambridge Healthtech Advisors Model Animal Systems: Emerging Applications and Commercial Opportunities in Drug Discovery and Development, report, 2004  

Both animal models and cellular assays are utilized. 

toxicogenomics: A compendium of gene expression data enhanced by complete proteomic analysis will enable investigators to probe the complexities of the mechanisms of normal genetic and metabolic pathways, and subsequently, to learn how disease occurs when these pathways malfunction. When combined with information on gene/protein groups, functional pathways and networks, and human genetic polymorphisms, these data will confer new knowledge of gene-environment interactions and human health risks. Homepage, NCTR National Center for Toxigenomics, NIEHS National Institute of Environmental Health Sciences, 2005 http://www.niehs.nih.gov/nct/home.htm

An approach to toxicology measuring how people's genomes respond to environmental stressors or toxicants.  Combines genome- wide gene expression profiling with protein expression patterns using bioinformatics to understand the role of gene- environment interactions in disease, understand how chemicals affect the expression of genes, characterize normal genetic and metabolic pathways, and learn how disease occurs when these pathways malfunction. CHA Cambridge Healthtech Advisors, Clinical Genomics: The Impact of Genomics on Clinical Trials and Medical Practice report, 2004

The study of the structure and output of the genome as it responds to adverse xenobiotic exposure. Ulrich RG. The toxicogenomics of nuclear receptor agonists. Current Opinion in Chemical Biology 7(4) 505- 510, August 2003

An emerging discipline that combines expertise in toxicology, genetics, molecular biology, and environmental health to elucidate the response of living organisms to stressful environments. Of particular interest to scientists in the field is the advancement of high- throughput and computational methodologies to study gene and protein expression at all levels, and the application of this knowledge to enhance our understanding and therapeutic management of human illnesses. The promise of toxicogenomics will become a reality as we begin to fully understand how subtle variations in the environment give rise to altered phenotypes that compromise organ and system functions.  NIEHS, EHP Toxicogenomics, Jan. 2003  http://ehp.niehs.nih.gov/txg/docs/2003/111-1T/eds/eds.html

The ability to predict the toxic effects of potential new drugs is crucial to prioritizing compound pipelines and eliminating costly failures in drug development. Toxicogenomics, which deals primarily with the effects of compounds on gene expression patterns in target cells or tissues, is emerging as a key approach in screening new drug candidates because it may reveal genetic signatures that can be used to predict toxicity in these compounds. Insight Pharma Reports Toxicogenomics: The Promise of Safer, Smarter Drug Development, 2005

The hybridization of functional genomics and molecular toxicology. Leming Shi “DNA Microarrays” 1998-2002 http://www.gene-chips.com/

From toxicology + genomics

Google = about 9,650 Sept. 10, 2003; about 27,700 June 7, 2004, about 1,050 Aug. 15, 2005, about 689,000 Oct. 25, 2006, about 567,000 Apr 5, 2007, about 309,000 OCt. 28, 2008, about 348,000 May 14, 2009

National Center for Toxicogenomics, NIEHS, US http://www.niehs.nih.gov/nct/home.htm

toxicoinformatics: An emerging scientific discipline that integrates approaches from multidisciplinary fields of bioinformatics, chemoinformatics, computational toxicology, informatics technologies and physiologically- based pharmacokinetic modeling with the objective of knowledge discovery and the elucidation of mechanisms of toxicity. NCTR's Center for Toxicoinformatics, National Center for Toxicological Research, FDA, 2003  http://www.fda.gov/nctr/science/centers/toxicoinformatics/

Google = about 161 Nov. 21, 2003; about 746 Nov 10, 2006, about 775 Apr 4, 2007, about 883 Oct. 28, 2008, about 2,610 May 14, 2009

toxicokinetics: Exploring alternate approaches for evaluating exposure in rat safety studies that do not require the use of satellite TK groups by collecting TK reports from Members, and then calculating exposure based on the full data sets, and comparing this to exposure calculated on simulated sparse datasets (i.e. subsets of the original data).  Two algorithms for calculating exposure on sparse datasets were evaluated.  Toxicokinetics TK Optimization: A CHA Case Study Multi-Company, Collaborative Project [report available?] http://www.chacorporate.com/pages/91_toxicokinetics_tk_optimization.cfm

Process of the uptake of potentially toxic substances by the body, the biotransformation they undergo, the distribution of the substances and their metabolites in the tissues, and the elimination of the substances and their metabolites from the body. Both the amounts and the concentrations of the substances are studied. The term has essentially the same meaning as pharmacokinetics, but the latter term should be restricted to the study of pharmaceutical substances. [IUPAC Compendium]

See also under pharmacokinetics: Pharmacogenomics

toxicology: Can be described, according to a U.S. National Library of Medicine online tutorial, as "the study of the adverse effects of chemicals or physical agents on living organisms." Such effects run the gamut from immediate death to subtle effects that manifest only months or years after exposure. Toxic substances may affect various levels of the body, such as a particular organ, cell type, or biomolecule. 

Narrower terms: biochemical toxicology, molecular toxicology, nanotoxicology 

toxicoproteomics: Toxicoproteomics is the use of global protein expression technologies to better understand environmental and genetic factors, both in episodes of acute exposure to toxicants and in the long-term development of disease. Integrating transcript, protein, and toxicology data is a major objective of the field of toxicogenomics. KB Tomer, DB Merrick, Toxicoproteomics: a parallel approach to identifying biomarkers Environmental Health Perspectives 2003 Aug;111(11): A578- 579.

Google = about 19,100 Nov 5, 2005; about 16,400 Nov 10, 2006, about 13,100 Apr. 5, 2006, about 8,230 Oct. 28, 2007, about 5,980 May 14, 2009

toxins:  Integrated Risk Information Systems, US Environmental Protection Agency http://www.epa.gov/iriswebp/iris/index.html

transcriptomics: In the context of toxicology studies, involves assessing changes in transcription initiation, processing, and degradation after chemical exposure using glass and membrane DNA microarrays and low- output tools, such as ribonuclease protection assays and real-time PCR.

uncertainty: Molecular Medicine

xenobiotic: A compound foreign to an organism. From the Greek xenox = foreign, bios = life. [IUPAC Medicinal Chemistry] Principal xenobiotics include drugs, carcinogens and various compounds that have been introduced into the environment by artificial means. IUPAC Bioinorganic

A key term in toxicology (means foreign substance) is used to identify clearly toxic substances, such as lead, or beneficial therapeutic agents, many of which become toxic at elevated dosage levels.  Drugs can generally be characterized as having a nontoxic or beneficial dose, a toxic dose, and a lethal dose. For example, two 650 mg aspirin tablets are usually beneficial, while seven tablets are usually toxic, and 60 tablets can be lethal. Similarly, a blood alcohol level of 0.05% is generally nontoxic, while 0.10% is toxic, and 0.50% can be lethal. However, it is important to note that such levels are averages, and individuals can manifest significant departures from the mean, depending on expression levels of key metabolic enzymes and the presence of polymorphisms that degrade or enhance the activity of these enzymes.

Bibliography
ATSDR Glossary, Agency for Toxic Substances & Disease Registry, http://www.atsdr.cdc.gov/glossary.html 2009
Insight Pharma Reports, Bayesian Forecasting of Phase III Outcomes: The Next Wave in Predictive Tools, June 2007  
Glossary of IRIS [Integrated Risk Information System] Terms, Environmental Protection Agency, 2009, 100+ terms http://www.epa.gov/ncea/iris/help_gloss.htm 
Insight Pharma Reports, Bayesian Forecasting of Phase III Outcomes: The Next Wave in Predictive Tools,  2007
Insight Pharma Reports, Cardiotoxicity issues, technologies and solutions for the future, 2008 http://www.chicorporate.com/reports_report.aspx?id=75178&r=558
Insight Pharma Reports  Outlook for Predictive Safety Technologies, 2006  http://www.insightpharmareports.com/reports/2006/74_PredSafety/overview.asp
IUPAC, Abbreviations and acronyms used in the Toxicology Literature, IUPAC Glossary of Toxicology, 2007  http://sis.nlm.nih.gov/enviro/iupacglossary/annex1.html 
IUPAC, Abbreviations and acronyms of names of International Bodies, IUPAC Glossary of Toxicology, 2007 http://sis.nlm.nih.gov/enviro/iupacglossary/annex2.html 
IUPAC, Explanatory dictionary of key terms used in toxicology, 2007 http://www.iupac.org/publications/pac/79/9/1583/
IUPAC, Glossary of terms used in toxicology, 2007 http://sis.nlm.nih.gov/enviro/iupacglossary/frontmatter.html  
IUPAC, Glossary for toxicokinetics of chemicals, 365 terms. http://www.iupac.org/publications/pac/2004/pdf/7605x1033.pdf  Published Pure & Applied Chemistry 76 (5): 1033-1082, 2004
IUPAC International Union of Pure and Applied Chemistry, GLOSSARY FOR CHEMISTS OF TERMS USED IN TOXICOLOGY Clinical Chemistry Division, Commission on Toxicology, Recommendations. Pure and Appl. Chem., 65 (9):  2003- 2122, 1993. 1200+ definitions.    http://www.iupac.org/reports/1993/6509duffus/index.html
WHO, Adverse Reaction Terminology, 2009 http://www.umc-products.com/graphics/3036.pdf 

Alpha glossary index
How to look for other unfamiliar  terms

IUPAC definitions are reprinted with the permission of the International Union of Pure and Applied Chemistry