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 Drug safety glossary & taxonomy
Evolving Terminologies for Emerging Technologies
Comments? Questions? Revisions? 
Mary Chitty MSLS
Last revised January 07, 2020

SCOPE NOTE Drug safety includes adverse events, immunogenicity, cardiotoxicity, hepatotoxicity, neurotoxicity, nephrotoxicity, toxicology, Phase IV/pharmacovigilance post marketing surveillance, preclinical drug safety.

Related glossaries include Biomarkers   Clinical trials   Pharmacogenomics   Regulatory

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
Related terms: adverse drug reaction ADR, drug interaction. See also pharmacovigilance, post-marketing surveillance 

adverse effect: Change in biochemistry, physiology, growth, development morphology, behavior, or lifespan of an organism which results in impairment of functional capacity or impairment of capacity to compensate for additional stress or increase in  to other environmental influences. Change in biochemistry, physiology, growth, development morphology, behavior, or lifespan of an organism which results in impairment of functional capacity or impairment of capacity to compensate for additional stress or increase in  to other environmental influences.  IUPAC Toxicology

adverse event terminology, Norman GoldFarb 2012 Journal of Clinical Research Best Practices 

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

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

Wikipedia   Related terms: adverse drug event ADE, drug interaction  

Ames test: This test for genotoxicity, developed in the 1970s, determines the reversion of a mutant his gene in Salmonella typhimurium when exposed to a genotoxic agent that causes base changes affecting the mutant gene.

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

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 

cardiotoxicity: 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: Tens of thousands of chemicals are currently in use, and hundreds more are introduced every year. Because current chemical testing is expensive and time consuming, only a small fraction of chemicals have been evaluated fully for potential human health effects.  EPA’s National Center for Computational Toxicology is working to figure out how to change the current approach used to evaluate the safety of chemicals. NCCT researchers integrate advances in biology, biotechnology, chemistry, and computer science to identify important biological processes that may be disrupted by the chemicals. 

drug metabolites: Guidance for Industry, Safety testing of drug metabolites, FDA, 2008 

drug safety: 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 & Availability, FDA  Information for consumers and health professionals on new drug warnings and other safety information, drug label changes, and shortages of medically necessary drug products.

CDER Drug Safety Priorities, FDA 2017

EMA: European Medicines Agency  Was EMEA.

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

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

ED 50:  Abbreviation for median effective dose. 

endocrine disruptors:  chemicals that can interfere with endocrine (or hormone) systems at certain doses. These disruptions can cause cancerous tumors, birth defects, and other developmental disorders.[1] Any system in the body controlled by hormones can be derailed by hormone disruptors. Specifically, endocrine disruptors may be associated with the development of learning disabilities, severe attention deficit disordercognitive and brain development problems; deformations of the body (including limbs); breast cancer, prostate cancer, thyroid and other cancers; sexual development problems such as feminizing of males or masculinizing effects on females, etc.[2]

Recently the Endocrine Society released a statement on endocrine-disrupting chemicals (EDCs) specifically listing obesity, diabetes, female reproduction, male reproduction, hormone-sensitive cancers in females, prostate cancer in males, thyroid, and neurodevelopment and neuroendocrine systems as being affected biological aspects of being exposed to EDCs.[3] The critical period of development for most organisms is between the transition from a fertilized egg into a fully formed infant. As the cells begin to grow and differentiate, there are critical balances of hormones and protein changes that must occur. Therefore, a dose of disrupting chemicals may do substantial damage to a developing fetus. The same dose may not significantly affect adult mothers. Wikipedia accessed 2018 Nov 19 

evidence based toxicology: This paper identifies deficiencies in some current practices of causation and risk evaluation by toxicologists and formulates an evidence-based solution. The practice of toxicology focuses on adverse health events caused by physical or chemical agents. Some relations between agents and events are identified risks, meaning unwanted events known to occur at some frequency. However, other relations that are only possibilities--not known to occur (and may never be realized) --also are sometimes called risks and are even expressed quantitatively. The seemingly slight differences in connotation among various uses of the word 'risk' conceal deeply philosophic differences in the epistemology of harm. We label as 'nomological possibilities' (not as risks) all predictions of harm that are known not to be physically or logically impossible. Some of these nomological possibilities are known to be causal. We term them 'epistemic'. Epistemic possibilities are risks. The remaining nomological possibilities are called 'uncertainties'. Distinguishing risks (epistemic relationships) from among all nomological possibilities requires knowledge of causation. Causality becomes knowable when scientific experiments demonstrate, in a strong, consistent (repeatable), specific, dose-dependent, coherent, temporal and predictive manner that a change in a stimulus determines an asymmetric, directional change in the effect.  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 

good pharmacovigilance practice:  EMA


idiosyncratic drug reactions, also known as type B reactions, are drug reactions that occur rarely and unpredictably amongst the population. This is not to be mistaken with idiopathic, which implies that the cause is not known. They frequently occur with exposure to new drugs, as they have not been fully tested and the full range of possible side-effects have not been discovered; they may also be listed as an adverse drug reaction with a drug, but are extremely rare. Wikipedia accessed August 12, 2018

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: is the ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human or animal. In other words, immunogenicity is the ability to induce a humoral and/or cell-mediated immune responses.  accessed 2017 Oct 16

Immunogenicity Assessment and Regulatory Approval of Biologics Achieving Assay Quality and Clinical Success of Novel Biologics APRIL 10-11, 2019 BOSTON MA Immunogenicity has always been a critical safety concern, especially when many biotherapeutics are becoming increasingly complex. Understanding and controlling immunogenicity-related risks are essential in the development of biotherapeutics to ensure meeting the regulatory requirements. The 12th Annual Immunogenicity Assessment and Regulatory Approval of Biologics conference brings industry, regulatory and scientific experts together to share best practices in assessing immunogenicity of novel biologics along with biosimilar products. The session will also discuss the challenges and solutions for addressing new regulatory guidelines in assay development and validation for cell and gene therapies.

Immunogenicity Case Studies and Clinical Management Interpretation and Understanding of Immunogenicity Data in Clinical Settings APRIL 8-9, 2019 BOSTON MA As the immunogenicity field is moving forward, closing the gap between clinicians and assay developers is essential in the success of biologic development and accelerates the adoption of new biologic therapies in patient treatments. This year, CHI’s Immunogenicity Case Studies and Clinical Management conference will focus on new case studies of novel biologics and emphasize on closing this gap by providing multiple viewpoints from clinicians, technology developers and regulators on how to use immunogenicity data in clinical settings.

immunoinformatics: the application of informatics techniques to molecules of the immune system. One of the key goals of immunoinformatics is the development of computer aided vaccine design (CAVD), or computational vaccinology, and its application to the search for new vaccines. Key to solving this challenge is the prediction of immunogenicity, be that at the level of epitope, subunit vaccine or attenuated pathogen. Flower DR, Doytchinova IA Immunoinformatics and the prediction of immunogenicity Appl Bioinformatics. 2002;1(4):167-176 .

The primary objective of this “Glossary of Terms Used in Immunotoxicology” is to give clear definitions for those who contribute to studies relevant to immunotoxicology but are not themselves immunologists. This applies especially to chemists who need to understand the literature of immunology without recourse to a multiplicity of other glossaries or dictionaries. The glossary includes terms related to basic and clinical immunology insofar as they are necessary for a self-contained document, and particularly terms related to diagnosing, measuring, and understanding effects of substances on the immune system. The glossary consists of about 1200 terms as primary alphabetical entries, and Annexes of common abbreviations, examples of chemicals with known effects on the immune system, autoantibodies in autoimmune disease, and therapeutic agents used in autoimmune disease and cancer. IUPAC mmunotoxicology recommendations, 2012

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

Lead Optimization for Drug Metabolism & Safety Tools and Strategies for Predicting, Evaluating and Building Safety into Drug Design APRIL 12, 2019 San Diego CA The more chemists know about how the structure of a compound can possibly impact its drug-like properties, the faster they can optimize it for drug development. Lead compounds in drug discovery need to be optimized for both efficacy and safety. Unfortunately, some of the adverse events related to drug metabolism, clearance, and drug-drug interactions (DDI) do not surface until much later in drug development. This unique one-day symposium on Lead Optimization for Drug Metabolism & Safety will bring together experts from chemistry, ADME, DMPK and pharmacology to talk about some of the factors that must be considered early in lead optimization, particularly for addressing safety concerns.

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, 2016 

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 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

nanotoxicology: Nanotoxicology invites contributions addressing research relating to the potential for human and environmental exposure, hazard and risk associated with the use and development of nano-structured materials. In this context, the term nano-structured materials has a broad definition, including ‘materials with at least one dimension in the nanometer size range’. These nanomaterials range from nanoparticles and nanomedicines, to nano-surfaces of larger materials and composite materials. The range of nanomaterials in use and under development is extremely diverse, so this journal includes a range of materials generated for purposeful delivery into the body (food, medicines, diagnostics and prosthetics), to consumer products (e.g. paints, cosmetics, electronics and clothing), and particles designed for environmental applications (e.g. remediation). It is the nano-size range if these materials which unifies them and defines the scope of Nanotoxicology.  While the term ‘toxicology’ indicates risk, the journal Nanotoxicology also aims to encompass studies that enhance safety during the production, use and disposal of nanomaterials. Well-controlled studies demonstrating a lack of exposure, hazard or risk associated with nanomaterials, or studies aiming to improve biocompatibility are welcomed and encouraged, as such studies will lead to an advancement of nanotechnology. Furthermore, many nanoparticles are developed with the intention to improve human health (e.g. antimicrobial agents), and again, such articles are encouraged. In order to promote quality. Aims and Scope, Nanotoxicology, Taylor & Francis

: toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on renal function. There are various forms,[1] and some drugs may affect renal function in more than one way. Nephrotoxins are substances displaying nephrotoxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the decreased renal function (e.g., heparin). Wikipedia accessed 2018 Aug 20

neurotoxicity: a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system.[1] It occurs when exposure to substance – specifically, a neurotoxin – alters the normal activity of the nervous system in such a way as to cause permanent or reversible damage to nervous tissue.[1] This can eventually disrupt or even kill neurons, which are cells that transmit and process signals in the brain and other parts of the nervous system.  … The term neurotoxicity implies the involvement of a neurotoxin; however, the term neurotoxic may be used more loosely to describe states that are known to cause physical brain damage, but where no specific neurotoxin has been identified. Wikipedia accessed 2018 Nov 10 the need for totally or partially replacing the animal toxicity assays with shorter-term, animal-free toxicological methods has become more and more compelling in the recent decades. In the field of drug design, one primary need is the early recognition of potentially toxic molecules. In fact, attrition due to nonclinical safety represents a major issue for the productivity of pharmaceutical research and development [1Blomme EAG, Will Y. Toxicology strategies for drug discovery: present and future. Chem Res Toxicol. 2016;29:473–504.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In other fields, new regulatory policies (e.g. registration, evaluation, authorization and restriction of chemical substances and cosmetics) tend to drastically reduce the use of animals.

As a consequence, there are considerable opportunities to accept ‘alternative’ approaches, both in silico (e.g. quantitative structure–activity relationships [QSAR]) and in vitro. This research is extremely active and has generated a large variety of approaches and proposals [2Worth A, Barroso J, Bremer S, et al. Alternative methods for regulatory toxicology – a state-of-the-art review. Ispra: European Commission. JRC Science and Policy Reports; 2014. [Google Scholar]]. Particularly relevant are large-scale funded programs, like the European Union projects safety evaluation ultimately replacing animal testing and EU-ToxRisk [3Daneshian M, Kamp H, Hengstler JG, et al. Highlight report: launch of a large integrated European in vitro toxicology project: EU-ToxRisk. Arch Toxicol. 2016;90:1021–1024.[Crossref][PubMed][Web of Science ®][Google Scholar]] and the US Environmental Protection Agency ToxCast project [4Kavlock RJ, Austin CP, Tice RR. Toxicity testing in the 21st century: implications for human health risk assessment. Risk Anal. 2009;29:485–487.[Crossref][PubMed][Web of Science ®] Emerging trends in technologies include new in vitro screening assays, transcriptomics, stem cells, engineered microscale physiological systems, 3D organotypic culture models, and small model organisms (such as zebra fish and Caenorhabditis elegans). A great emphasis is being given to in-depth explorations of the mechanisms of toxicological action: the rationale is to identify the key events in the toxicity pathways and then devise new in vitro tests that could specifically measure those events. The ToxCast/Tox21 project [4Kavlock RJ, Austin CP, Tice RR. Toxicity testing in the 21st century: implications for human health risk assessment. Risk Anal. 2009;29:485–487.[Crossref][PubMed][Web of Science ®][Google Scholar]] and the Adverse Outcome Pathway (AOP) concept and related activities [2Worth A, Barroso J, Bremer S, et al. Alternative methods for regulatory toxicology – a state-of-the-art review. Ispra: European Commission. JRC Science and Policy Reports; 2014. [Google Scholar],5Ankley GT, Bennett RS, Erickson RJ, et al. Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem. 2011;29:730–741.[Crossref][Web of Science ®][Google Scholar]] are examples of this new impetus. Another challenge is to develop tools for integrating multiple types of data from diverse experimental systems into unified risk assessment paradigms. Romualdo Benigni (2016) Predictive toxicology today: the transition from biological knowledge to practicable models, Expert Opinion on Drug Metabolism & Toxicology, 12:9, 989-992, DOI: 10.1080/17425255.2016.1206889

particulates - detection & characterization:   January 21-22 2020 • San Diego, CA Program   Some of the hot topics for this year will be new and novel technologies for aggregates and impurities in gene therapies, AAVs, virus and pathogen detection, host cell proteins, lipases and enzymatic degradation, other particles and aggregations, and chemistry and manufacturing controls (CMC) |

pharmacoepidemiology: the study of the uses and effects of drugs in well-defined populations.[1][2]  To accomplish this study, pharmacoepidemiology borrows from both pharmacology and epidemiology. Thus, pharmacoepidemiology is the bridge between both pharmacology and epidemiology. Pharmacology is the study of the effect of drugs and clinical pharmacology is the study of effect of drugs on clinical humans. Part of the task of clinical pharmacology is to provide a risk benefit assessment by effects of drugs in patients: doing the studies needed to provide an estimate of the probability of beneficial effects on populations, or assessing the probability of adverse effects on populations.  Other parameters relating to drug use may benefit epidemiological methodology. Pharmacoepidemiology then can also be defined as the transparent application of epidemiological methods through pharmacological treatment of conditions to better understand the conditions to be treated. Wikipedia accessed 2018 March 1

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, 2016 

pharmacovigilance:  is defined as 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 2011 

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

Good Pharmacovigilance Practices, FDA 2005
Wikipedia   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. 
FDA Postmarketing surveillance programs


See also clinical trials, phase I, II, III,  post approval drug safety
Broader term: drug safety 

Postmarket Drug Safety Information for Patients and Providers

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 

predictive toxicity Predictive toxicology plays an important role in the assessment of toxicity of chemicals and the drug development process. While there are several well-established in vitro and in vivo assays that are suitable for predictive toxicology, recent advances in high-throughput analytical technologies and model systems are expected to have a major impact on the field of predictive toxicology. … Computational models for predictive toxicology, needs for further refinement and obstacles to expand computational models to include additional classes of chemical compounds are highlighted. Functional and comparative genomics approaches in predictive toxicology are discussed with an emphasis on successful utilization of recently developed model systems for high-throughput analysis. The advantages of three-dimensional model systems and stem cells and their use in predictive toxicology testing are also described. Zhang L, McHale CM, Greene N, et al. Emerging approaches in predictive toxicology. Environ Mol Mutagen. 2014;55(9):679-88.  

FDA, Predictive Toxicology Road Map 2017  FDA's Predictive Toxicology Roadmap 

the most important challenge in toxicology is to develop tools and approaches that predict the toxicity potential of chemicals in an adequately reliable manner before humans, or any other living organisms, have been exposed to them. …Realization of this most important goal needs scientists with versatile skills and from different backgrounds, using a variety of tools and approaches. Perhaps the most urgent task is to refine, reduce, and replace testing systems based on mammalian species by submammalian or in vitro systems. The current paradigm of toxicity testing is heavily dependent on animal tests that were developed decades ago. Predictive toxicity: grand challenges. Front Pharmacol. 2010; 1:3. Published 2010 Apr 23. doi:10.3389/fphar.2010.00003

Protein aggregation and stability in Biopharmaceutical Products 2019 May 3-4 Boston MA The phenomenon of protein aggregation is a complex conundrum that impacts biopharmaceutical development at virtually every stage. All mechanisms of aggregation are not conclusively known, but the industry must use every effort to characterize and control these conditions, applying a rapidly changing landscape of assays, instrumentation, formulation strategies and process steps. The PEGS Protein Aggregation and Stability in Biopharmaceutical Products offers important scientific updates and a forum for dialog among the stakeholders in this challenging arena.  Program

Protein Aggregation and Emerging Analytical Tools

Protein Aggregation and Emerging Analytical Tools  January 23-24 , 2020 • San Diego, CA Peptalk  covers latest trends, challenges and solutions in understanding, characterization and mitigation of problems generated by protein aggregation in biopharmaceuticals. This conference will feature in-depth case studies, new and unpublished data and interactive discussions on immunogenicity of aggregates, mechanisms of aggregation, new tools for detection and quantitation of aggregates, and how the data is used in regulatory filings. It will also discuss mechanistic understanding of protein aggregation and present case studies on prevention of particle formation by engineering and formulation approaches, aggregation in ADCs, bipecifics, impact of aggregation on production, aggregates as a factor for immunogenicity, and approaches for improvement of biophysical properties of protein solutions.

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 : A Risk Evaluation and Mitigation Strategy (REMS) is a drug safety program that the U.S. Food and Drug Administration (FDA) can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks. REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication. While all medications have labeling that informs health care stakeholders about medication risks, only a few medications require a REMS.

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

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 

Sentinel Initiative:  In May 2008, the FDA launched the Sentinel Initiative to create a national electronic system, the Sentinel System, for medical product safety surveillance. The first phase of this initiative was the Mini-Sentinel Pilot to inform the development of the Sentinel System. In September 2014, the FDA began transitioning from the Mini-Sentinel phase to the full Sentinel System, which officially launched in February 2016. We will continue to expand access to new data types and develop analytic methods to enhance our safety surveillance capabilities and allow the Agency to rapidly address the variety of safety questions that may come up in the future.

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

susceptibility: Molecular diagnostics

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  

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   Related terms: -Omes & -omics  cross-omics

Therapeutic Index: An indicator of the benefits and risks of treatment. Year introduced: 2018 MeSH  

Therapeutic Index, Drug: The ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response. MeSH  Related terms: ED 50, LD 50 Lethal Dose 50.

toxicity testing: An important part of the drug- lead- optimization process in which investigational compounds are tested for their potential to cause side effects. Both animal models and cellular assays are utilized. 

toxicity tests: An array of tests used to determine the toxicity of a substance to living systems. These include tests on clinical drugs, foods, and environmental pollutants. MeSH 1995

toxicogenomics: 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

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.

toxicokinetics: 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 
Wikipedia  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 

toxinology: In recent years, the field of toxinology has expanded substantially. On the one hand it studies venomous animals, plants and micro organisms in detail to understand their mode of action on targets. While on the other, it explores the biochemical composition, genomics and proteomics of toxins and venoms to understand their three interaction with life forms (especially humans), development of antidotes and exploring their pharmacological potential. Toxinology book series  

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.

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.

Drug safety resources
ATSDR Glossary, Agency for Toxic Substances & Disease Registry, 2009-2016
ICH International Council on Harmonisaiton Drug safety guidances

IPCS International Program on Chemical Safety/ISEA International Society for Exposure Analysis Glossary  37 terms

IUPAC, Abbreviations and acronyms of names of International Bodies, IUPAC Glossary of Toxicology, 2007 
IUPAC International Union of Pure and Applied Chemistry, CHEMISTRY AND HUMAN HEALTH DIVISION, IUPAC GLOSSARY OF TERMS USED IN TOXICOLOGY, 2nd EDITION - IUPAC RECOMMENDATIONS 2007 Published in Pure Appl. Chem., Vol. 79, No. 7, pp. 1153-1344, 2007
IUPAC  International Union of Pure and Applied Chemistry, Glossary of Terms used in Bioinorganic Chemistry, Recommendations, 1997. 450+ definitions.

IUPAC Glossary of terms in immunotoxicology, 2012
IUPAC, Glossary for toxicokinetics of chemicals, 365 terms.  Published Pure & Applied Chemistry 76 (5): 1033-1082, 2004
Nature Drug Safety
WHO, Adverse Reaction Terminology, 2009 

Drug safety Conferences
World Pharmaceutical Congress WPC
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How to look for other unfamiliar  terms

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

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