Ministry of Public Health General Directorate of ... ... microbiologic origin ... The evaluation of...

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Glossary of terms used in Pharmacovigilance 2015 Ministry of Public Health General Directorate of Pharmaceutical Affairs Avicenna Pharmacy Institute Medicine Safety Committee Glossary of terms used in Pharmacovigilance Adopted from: Uppsala Monitoring Centre (UMC) April, 2015

Transcript of Ministry of Public Health General Directorate of ... ... microbiologic origin ... The evaluation of...

Glossary of terms used in Pharmacovigilance 2015

Ministry of Public Health

General Directorate of Pharmaceutical Affairs Avicenna Pharmacy Institute Medicine Safety Committee

Glossary of terms used in Pharmacovigilance

Adopted from: Uppsala Monitoring Centre (UMC)

April, 2015

Glossary of terms used in Pharmacovigilance 2015

Contents Absolute risk ....................................................................................................... 7

Adverse Event (AE) ............................................................................................. 7

Unexpected adverse event or unexpected suspected adverse reaction ...................... 7

Adverse Drug Effect ............................................................................................ 8

Adverse Drug Reaction (ADR) ............................................................................. 8

Classification of ADRs ......................................................................................... 8

Allopathy .......................................................................................................... 10

Association ....................................................................................................... 10

Attributable risk ................................................................................................ 10

Benefit .............................................................................................................. 10

Benefit - risk analysis ........................................................................................ 10

Biological products ........................................................................................... 11

Causal relationship ........................................................................................... 12

Causality assessment ........................................................................................ 12

WHO-UMC Causality Categories ....................................................................... 12

Causality & Correlation ..................................................................................... 13

European ABO system ...................................................................................... 14

Caveat document ............................................................................................. 14

CemFlow ........................................................................................................... 14

Clinical trial ....................................................................................................... 15

Cohort Event Monitoring .................................................................................. 15

Compliance ....................................................................................................... 15

Control group ................................................................................................... 15

Critical terms .................................................................................................... 15

Data mining ...................................................................................................... 15

De-challenge ..................................................................................................... 16

Glossary of terms used in Pharmacovigilance 2015

Disproportionality analysis ............................................................................... 16

Drug interaction................................................................................................ 16

Effectiveness/risk ............................................................................................. 17

Efficacy.............................................................................................................. 17

Epidemiology .................................................................................................... 17

Essential medicines .......................................................................................... 17

EudraVigilance .................................................................................................. 18

Excipients .......................................................................................................... 18

Formulary ......................................................................................................... 18

Frequency of ADRs ........................................................................................... 18

Generic (multisource product) ......................................................................... 19

Harm ................................................................................................................. 19

Herbal medicine ............................................................................................... 19

Homeopathy ..................................................................................................... 19

Hypersensitivity ................................................................................................ 19

Intensity of ADR ................................................................................................ 20

Information component (IC) ............................................................................. 20

Incidence .......................................................................................................... 20

Individual Case Safety Report (ICSR) ................................................................ 21

Intolerance ....................................................................................................... 21

Life-threatening adverse event or life-threatening suspected adverse reaction ......... 21

MedDRA............................................................................................................ 21

Medical error .................................................................................................... 22

Medicinal Product ............................................................................................ 22

National pharmacovigilance centers ................................................................ 24

Odds.................................................................................................................. 24

Odds ratio ......................................................................................................... 24

Glossary of terms used in Pharmacovigilance 2015

Omega (Ω) ........................................................................................................ 24

OTC (Over the Counter) medicine .................................................................... 25

PaniFlow ........................................................................................................... 25

Periodic Safety Update Report (PSUR) ............................................................. 25

Pharmaceutical Formulation ............................................................................ 25

Pharmacoepidemiology .................................................................................... 26

Pharmacology ................................................................................................... 26

Pharmacovigilance ............................................................................................ 26

Phocomelia ....................................................................................................... 26

Phytotherapy .................................................................................................... 26

Placebo ............................................................................................................. 26

Polypharmacy ................................................................................................... 26

Post-marketing ................................................................................................. 27

Predisposing factors ......................................................................................... 27

Pre-marketing ................................................................................................... 27

Prescription EventMonitoring (PEM)................................................................ 27

Prescription Only Medicine (POM) ................................................................... 27

Prevalence ........................................................................................................ 27

Prophylaxis ....................................................................................................... 27

Rational drug use .............................................................................................. 28

Rechallenge ...................................................................................................... 28

Record linkage .................................................................................................. 28

Reference risk ................................................................................................... 28

Regulatory authority ......................................................................................... 28

Relative risk ...................................................................................................... 29

Risk ................................................................................................................... 29

Serious vs. Severe Adverse Event or Reaction .................................................. 29

Glossary of terms used in Pharmacovigilance 2015

Serious adverse event or serious suspected adverse reaction ................................ 30

Side effect ......................................................................................................... 30

Signal ................................................................................................................ 30

Spontaneous reporting ..................................................................................... 31

Summary of Product Characteristics (SPC) ....................................................... 31

Suspected Adverse Drug Reactions .................................................................. 31

Thalidomide ...................................................................................................... 31

Time-Independent Reactions ........................................................................... 31

Time-Dependent Reactions .............................................................................. 32

Traditional medicines ....................................................................................... 33

Unexpected adverse reaction ........................................................................... 34

VigiBase ............................................................................................................ 34

VigiFlow ............................................................................................................ 34

Vigimed ............................................................................................................. 34

VigiMine ............................................................................................................ 34

VigiSearch ......................................................................................................... 34

WHO-ART .......................................................................................................... 34

WHO Drug Dictionary (WHO DD) ..................................................................... 35

Benefit risk ........................................................................................................ 35

Glossary of terms used in Pharmacovigilance 2015

Absolute risk Risk in a population of exposed persons; the probability of an event affecting members of a particular population (e.g. 1 in 1,000). Absolute risk can be measured over time (incidence) or at a given time (prevalence). Also see Attributable risk and Relative risk.

Adverse Event (AE) Any untoward medical occurrence that may present during treatment with a pharmaceutical product, but which does not necessarily have a causal relationship with this treatment. "Reasonable possibility" means there is evidence to suggest a causal relationship between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.

Unexpected adverse event or unexpected suspected adverse reaction

An adverse event or suspected adverse reaction is considered "unexpected" if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure listed only cerebral vascular accidents. "Unexpected," as used in this definition, also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation. Also see adverse reaction and Side Effect. Synonym: Adverse experience

Glossary of terms used in Pharmacovigilance 2015

Adverse Drug Effect An adverse drug event (ADE) is an injury to the patient resulting from

use of medication.

Adverse Drug Reaction (ADR) A response which is noxious and unintended, and which occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function. (WHO, 1972). An adverse drug reaction, contrary to an adverse event, is characterized by the suspicion of a causal relationship between the drug and the occurrence, i.e. judged as being at least possibly related to treatment by the reporting or a reviewing health professional. In the EU Directive 2010/84, which will become applicable in July 2012 an adverse reaction is defined as: A response to a medicinal product which is noxious and unintended. This can happen without an error, e.g. when a person has an allergy to the medicine but has never shown previous signs or risk factors for this allergy. However an error could be said to have occurred if a previous allergy was ignored and the patient was still given the drug. An ADR may therefore not necessarily be due to a medical error although it could be. A less studied medication error is the misdiagnosis of a disease when the real cause is a side effect of a medication.

Classification of ADRs Adverse drug reactions may be classified according to cause or severity. Based on clinical, pharmacological and epidemiological criteria, there are two basic categories of adverse drug reactions: Type A and Type B effects. Other classifications also include Type C - F effects. Types A & B were proposed in 1970, and other types were subsequently proposed when the first two proved insufficient to classify ADRs. Each type needs different methods for detection and study.

Glossary of terms used in Pharmacovigilance 2015

Type A [Augmented] refers to predictable dose-dependent responses which are exaggerated pharmacological actions at usual therapeutic doses. This could occur in everyone if enough of the drug is given because they are due to excess of normal, predictable dose-related, e.g. postural hypotension, hypoglycemia, hypokalemia etc. There are in many instances avoidable. Type B [Bizarre] refers to unpredictable, non-dose dependent, novel responses to a drug occurs only in some people e.g. fixed dose reaction of sulphonamides. Most times there are unavoidable. c) Type C is associated with the long term use of a drug and is related to cumulative use (C for continuous or chronic). It is chronic and of delayed onset. It tend to be both serious and (relatively) common and have profound effect on public health e.g. NSAIDS-induced renal failure, oral contraceptive induced diabetic micro-angiopathy and breast tumors. Type D refers to a delayed type of reaction (D for delayed) such as carcinogenesis, effects concerned with reproduction (impaired fertility), teratogenesis, tardive dyskinesia and peri- and postnatal adverse drug reactions. Uncommon, usually dose-related and occur sometime after drug use e.g. adenocarcinoma in daughters of women who have taken diethylstilboestrol, bladder cancers following long term cyclophosphamide, gene toxicity of some drugs, carcinoma of the renal pelvis following phenacetin etc. Type E refers to withdrawal or end of use adverse drug reactions (E for end of use). Uncommon and related to discontinuation that is too abrupt e.g. Addisonian crisis (adrenal (insufficiency) following steroid withdrawal, opiate withdrawal syndrome, rebound convulsions on withdrawal of carbamazepine in non-epileptic patients, myocardial infarction following beta blocker withdrawal. Type F refers to unexpected failure of therapy (F for failure). It is common, often dose related and caused by drug interactions e.g. inadequate dose of oral contraceptive or concomitant administration with enzyme –inducing drugs.

Glossary of terms used in Pharmacovigilance 2015

Allopathy Non-traditional, western scientific therapy, usually using synthesized ingredients, but may also contain a purified active ingredient extracted from a plant or other natural source; usually in opposition to the disease. Also see Homeopathy.

Association Events associated in time but not necessarily linked as cause and effect.

Attributable risk Difference between the risk in an exposed population (absolute risk) and the risk in an unexposed population (reference risk). Also referred to as Excess risk.Attributable risk is the result of an absolute comparison between outcome frequency measurements, such as incidence.

Benefit An estimated gain for an individual or a population. Also see Effectiveness/Risk.

Benefit - risk analysis Examination of the favorable (beneficial) and unfavorable results of undertaking a specific course of action. (While this phrase is still commonly used, the more logical pairings of benefit-harm and effectiveness-risk are slowly replacing it). Factors Influencing Benefit-Risk Assessment

1. Stakeholders and constituencies: Patients, physicians, pharmaceutical companies, ethics committees, regulatory authorities, other public health bodies, insurers, consumer groups and others may have very different perspectives. For example, two patients exposed to (and knowing about) the same benefits and risks may have different perceptions of, or thresholds for accepting, the risks, and thereby make different choices.

Glossary of terms used in Pharmacovigilance 2015

2. Nature of the problem: When a major new potential safety-problem arises, the need for urgent action to protect the public from a possibly serious hazard must be weighed against the need for additional data that might provide more certainty or confidence in the analyses and conclusions.

3. Indication for drug use and population under treatment:

A drug may be given for a life-threatening condition or a self-limiting disease; the acceptable risk for the former will undoubtedly be the higher.

Certain target sub-populations for the medicine may respond differently owing to ethnic differences in pharmacodynamics or pharmacokinetics or to medical-cultural influences.

4. Constraints of time, data and resources: When regulatory needs demand urgent attention, a comprehensive, comparative benefit-risk analysis may be difficult. This is especially the case if sufficient data on comparator drugs or other modalities (e.g., surgery) cannot be obtained reasonably quickly.

5. Economic issues:

Some economists have suggested that ‘‘economic efficiency’’ (difference between benefits and costs) should be a fundamental criterion for decisions on health and safety regulation, and have offered principles for the use of benefit-cost analyses or benefit-risk-cost analyses. Though it is not recommended to consider economic outcomes in the benefit-risk assessment.

Once it is established that conventional benefit-risk evaluation shows no significant differences between different products, cost may be one basis for choosing among them for a patient who responds equally to them.

Biological products Medical products prepared from biological material of human, animal or microbiologic origin (such as blood products, vaccines, insulin).

Glossary of terms used in Pharmacovigilance 2015

Causal relationship A relationship between one phenomenon or event (A) and another (B) in which A precede and causes B. In pharmacovigilance; a medicine causing an adverse reaction. Synonym: Causality

Causality assessment The evaluation of the likelihood that a medicine was the causative agent of an observed adverse reaction. Causality assessment is usually made according established algorithms.

WHO-UMC Causality Categories Causality Term Assessment Criteria 1. Certain

a) A clinical event, including laboratory test abnormality, occurring in a plausible time relationship to drug administration, Cannot be explained by concurrent disease or other drugs or chemicals.

b) The response to withdrawal of the drug (de-challenge) should be clinically plausible (i.e. pharmacologically, pathologically)

c) The event must be definitive pharmacologically or phenomenologically (i.e. an objective & specific medical disorder or a recognized pharmacological phenomenon). E.g. grey baby syndrome and chloramphenicol.

d) Re-challenge satisfactory if necessary

2. Probable/ Likely

a) A clinical event, including laboratory test abnormality, with a reasonable* time relationship / sequence to administration of the drug,

b) Unlikely to be attributed to concurrent disease or other drugs or chemicals,

Glossary of terms used in Pharmacovigilance 2015

c) Follows a clinically reasonable response on withdrawal (de-challenge).

d) Re-challenge information is not required to fulfill this definition.

3. Possible a) A clinical event, including laboratory test abnormality, with a

reasonable time sequence to administration of the drug, but given?

Causality & Correlation Bradford Hill Criteria- Austin Bradford Hill outlines the minimal conditions needed to establish a causal relationship between to items as follows:

1. Temporal Relationship: Exposure always precedes the outcome. If the drug causing the ADR, the ADR must occur after the drug intake, not before drug intake.

2. Strength of association: The stronger the association (established by appropriate statistical test), the more likely the relation of drug to ADR.

3. Dose-Response Relationship (Biological gradient): If increasing amount of exposure increases the risk- a strong evidence for a causal relationship.

4. Consistency: If a relation is causal, it is expected to find it consistently in different studies and in different population.

5. Plausibility: There should be some theoretical basis for positioning an association b/w a Drug and ADR. The association has to be in line with currently accepted understanding of patho-physiological processes.

6. Analogy/ Alternate Explanation: In analyzing whether an association is causal, it is necessary to effectively rule out other alternate explanations.

7. Experimental Evidence: Repeatability/ reproducibility by scientific method.

8. Specificity: Specificity is established when a single cause produces a single effect. However, absence of specificity in no way negates a causal relationship, indeed, causality is most often multiple.

Glossary of terms used in Pharmacovigilance 2015

9. Coherence: The association should be compatible with existing theory and knowledge. However, this should not lead to conservative complacency. The change in accepted theories are known as Paradigm Shift.

European ABO system The European ABO system of causality assessment was proposed by the European Union (EU) pharmacovigilance working parties as a step towards harmonization in drug regulation in the EU countries. The three causality categories are as follows: Category A: Reports including good reasons and sufficient documentation to assume a causal relationship, in the sense of plausible, conceivable, likely, but not necessarily highly probable. Category B: Reports containing sufficient information to accept the possibility of a causal relationship, in the sense of not impossible and not unlikely, although the connection is uncertain and may be even doubtful, e.g. because of missing data, insufficient evidence or the possibility of another explanation. Category O: Reports where causality is, for one or another reason, not assessable, e.g. because of missing or conflicting data.

Caveat document The formal advisory warning accompanying data release from the WHO Global ICSR Database: it specifies the conditions and reservations applying to interpretations and use of the data.

CemFlow Software developed by UMC for collection and analysis of data in Cohort Event Monitoring. Also see Cohort Event Monitoring.

Glossary of terms used in Pharmacovigilance 2015

Clinical trial A systematic study on pharmaceutical products in human subjects (including patients and other volunteers) in order to discover or verify the effects of and/or identify any adverse reaction to investigational products, and/or to study the absorption, distribution, metabolism and excretion of the products with the objective of ascertaining their efficacy and safety.

Cohort Event Monitoring Cohort Event Monitoring (CEM) is a prospective, observational study of events that occur during the use of medicines, for intensified follow-up of selected medicinal products phase. Patients are monitored from the time they begin treatment, and for a defined period of time. See also Prescription Event Monitoring.

Compliance Faithful adherence by the patient to the prescriber’s instructions.

Control group The comparison group in drug-trials not being given the studied drug.

Critical terms Some of the terms in WHO-ART are marked as ‘Critical Terms’. These terms either refer to or might be indicative of serious disease states, and warrant special attention, because of their possible association with the risk of serious illness which may lead to more decisive action than reports on other terms. Also see Serious adverse event or reaction.

Data mining A general term for computerized extraction of potentially interesting patterns from large data set, often based on statistical algorithms. A related term with essentially the same meaning is ‘Pattern discovery’.

Glossary of terms used in Pharmacovigilance 2015

In pharmacovigilance, the commonest application of data mining is so called disproportionality analysis, for example using the Information component (IC). See also Disproportionality analysis, Information component, Omega.

De-challenge The withdrawal of a drug from a patient; the point at which the continuity, reduction or disappearance of adverse effects may be observed.

Disproportionality analysis Screening of ICSR databases for reporting rates which are higher than expected. For drug-ADR pairs, common measures of disproportionality are the Proportional Reporting Ratio (PRR), the Reporting Odds Ratio (ROR), The Information Component (IC), and the Empirical Bayes GeometricalMean (EBGM). There are also disproportionalitymeasures for drug-drug- ADR triplets, such as Omega (Ω). See also Information component, Omega.

Drug interaction Drug interaction is the modification of the action of one drug by another as a result of one or more of three different kinds of mechanism: a) pharmaceutical; b) pharmacodynamic and c) pharmacokinetic. Drug interactions can be useful, of no consequence, or harmful. Drug interaction is important because, whereas judicious use of more than one drug at a time can greatly benefit patients, adverse interaction are not uncommon, and may be catastrophic, yet are often avoidable. Example is unexpected interaction between lopinavir and rosuvastatin which led to a 4.7-fold increase in the rosuvastatin plasma levels with associated risk of statin induced myopathies coupled with a diminished lipid lowering effect since the statin exerts its effect in the liver. Myocardial infarction is usually caused by white thrombus forming on a ruptured atheromatous plaque in a coronary artery. Such thrombi consist of fibrin and platelet aggregates, and studies have show that

Glossary of terms used in Pharmacovigilance 2015

streptokinase (a fibrinolytic drug) and aspirin (which inhibits platelet function) each improve outcome in patients with myocardial infarction, and the combination of aspirin with streptokinase has an additive effect. Several other examples of this kind of synergy are available in practice.

Effectiveness/risk The balance between the rates of effectiveness of a medicine versus the risk of harm is a quantitative assessment of the merit of a medicine used in routine clinical practice. Comparative information between therapies is most useful. This is more useful than the efficacy and hazard predictions from pre-marketing information that is limited and based on selected subjects.

Efficacy The ability of a drug to produce the intended effect as determined by scientific methods, for example in pre-clinical research conditions (opposite of hazard). See also Absolute risk, Reference risk, Attributable risk and Relative risk.

Epidemiology The science concerned with the study of the factors determining and influencing the frequency and distribution of disease, injury and other health-related events and their causes in a defined human population for the purpose of establishing programs to prevent and control their development and spread (Dorland’s IllustratedMedical Dictionary). Also see Pharmacoepidemiology.

Essential medicines Essential medicines are those that satisfy the priority health care needs of the population. They are selected with due regard to public health relevance, evidence on efficacy and safety, and comparative cost-effectiveness. See http://www.who.int/selection_medicines/en/

Glossary of terms used in Pharmacovigilance 2015

EudraVigilance The European Union data-processing network and management system, established by the EuropeanMedicines Agency (EMA) to support the electronic exchange, management, and scientific evaluation of Individual Case Safety Reports related to all medicinal products authorized in the European Economic Area (EEA). EudraVigilance also incorporates data analysis facilities.

Excipients All materials included to make a pharmaceutical formulation (e.g. a tablet) except the active drug substance(s). An excipient can be defined as any material, other than the therapeutically active substances, present in a pharmaceutical formulation. Excipients provide bulk; assist in the manufacture of a formulation (for example, by reducing the stickiness of a powder), control the rate at which a tablet disintegrates, provide a protective coating, inhibit degradation of the active substance during storage, mask the taste of a medicine, provide coloring, and control the rate of release of the medicine. They can cause adverse effects.

Formulary A listing of medicinal drugs with their uses, methods of administration, available dose forms, side effects, etc, sometimes including their formulas and methods of preparation.

Frequency of ADRs In giving an estimate of the frequency of ADRs the following standard categories are recommended: Very common* > 10% Common (frequent) >1% and <10%

Glossary of terms used in Pharmacovigilance 2015

Uncommon (infrequent) >0.1% and < 1% Rare >0.01% and <0.1% Very rare* <0.01% * Optional categories

Generic (multisource product) The term ‘generic product’ has somewhat different meanings in different jurisdictions. Generic products may be marketed either under the non-proprietary approved name or under a new brand (proprietary) name. They are usually intended to be interchangeable with the innovator product, which is usually manufactured without a license from the innovator company and marketed after the expiry of patent or other exclusivity rights.

Harm The nature and extent of actual damage that could be caused by a drug. Not to be confused with risk.

Herbal medicine Includes herbs, herbal materials, herbal preparations and finished herbal products.

Homeopathy Homeopathy is a therapeutic system which works on the principle that ‘like treats like’. An illness is treated with a medicine which could produce similar symptoms in a healthy person. The active ingredients are given in highly diluted form to avoid toxicity. Homeopathic remedies are virtually 100% safe. Also see Allopathy.

Hypersensitivity Hypersensitivity has been defined as:

An allergic reaction to a drug or other stimulus

Glossary of terms used in Pharmacovigilance 2015

A qualitatively normal response that occurs at alower dose or concentration of the drug than usual

A state of altered reactivity in which the body reacts with an exaggerated or inappropriate immune response to what is perceived to be a foreign substance

A reaction that is characterized by the fact that a marked adverse bodily response may be evoked by some specific substance or agent that (in similar amounts) has no such effect on most individuals

Intensity of ADR The seriousness of an adverse drug reaction is a measure of the extent to which the reaction can or does cause harm. In contrast the intensity (severity) of ad adverse drug reaction is a measure of the extent to which the adverse effect develops in an individual. For example ventricular tachycardia or hepatic impairment of urine by rifampicin. Even if very pronounced is not serious.

Information component (IC) The Information component (IC) measures the disproportionality in the reporting of a drug- ADR pair in an ICSR database, relative to the reporting expected based on the overall reporting of the drug and the ADR. Positive IC values indicate higher reporting than expected. The IC has also been implemented on electronic health records, to detect interesting temporal relationships between drug prescriptions and medical events.

Incidence Number of new cases of an outcome which develop over a defined time period in a defined population at risk.

Glossary of terms used in Pharmacovigilance 2015

Individual Case Safety Report (ICSR) A report that contains ‘information describing a suspected adverse drug reaction related to the administration of one or more medicinal products to an individual patient.

Intolerance Intolerance has been defined as: A greater than expected quantitative response to a dose of a drug an individual with a non-allergic qualitatively abnormal response has an idiosyncrasy; sensitivity, as to a drug. However, the term ‘tolerance’ has a specific pharmacological meaning, namely “diminished sensitivity to a drug resulting from previous exposure to that drug or a related drug (cross-tolerance)”. The term ‘intolerance’ also suggests that a patient is unable to tolerate an adverse effect, which is not necessarily so, and it adds nothing beyond what is implied in the term ‘adverse reaction’. Intolerance is also sometimes confusingly equated with hypersensitivity. We believe that the term ‘intolerance’ has no useful place in descriptions of adverse reactions to medicinal products, although it may have a role in describing adverse reactions to foods.

Life-threatening adverse event or life-threatening suspected

adverse reaction An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death.

MedDRA MedDRA is the Medical Dictionary for Regulatory Activities.WHO-ART MedDRA is Medical Dictionary for Regulatory Activities developed by ICH, and maintained by MSSO on behalf of ICH, the WHO Adverse Reactions Terminology, is now mapped to MedDRA.

Glossary of terms used in Pharmacovigilance 2015

A clinically-validated medical terminology, applicable to all phases of drug development excluding animal toxicology

Important for the electronic transmission of adverse events reporting, both in the pre- and post- marketing areas, as well as in the coding of clinical trial data

It is a standard dictionary that has already been adopted by most of the regulatory agencies and regulators

Medical error “An unintended act (either of omission or commission) or one that does not achieve its intended outcomes.” A medication error is any preventable event occurring from the inappropriate use of medication that has the potential to cause harm. Errors with medication can occur at several points of service in the hospital and even with the patients at home. Medication errors can lead to adverse drug reactions and drug interactions.

Medicinal Product The term ‘medicinal product’ was defined in an EU directive (2001/83/EC) as:

I. any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or

II. any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.

The meaning of ‘substance’ here is further defined as including any matter, irrespective of origin human, animal, vegetable, or chemical. Other definitions, such as those used in Australia and New Zealand, are similar and often refer to the EU definition. However, the EU definition omits some important uses of medicinal products, including their use as

Glossary of terms used in Pharmacovigilance 2015

placebos. Confusingly, the term ‘investigational medicinal product’ has been defined in relation to clinical trials for the purposes of the Clinical Trials Directive mentioned above as being: “a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorization but used or assembled (formulated or packaged) in a way different from the authorized form, or when used for an unauthorized indication, or when used to gain further information about the authorized form”. Therefore, we propose the following definition which describes what a medicinal product is and what it does: ‘A medicinal product is one that contains a com- pound with proven biological effects, plus excipients, or excipients only; it may also contain contaminants. The active compound is usually a drug or pro-drug but may be a cellular element. A medicinal product is one that is intended to be taken by or administered to a person or animal for one or more of the following reasons:

1. as a placebo; 2. to prevent a disease; 3. to make a diagnosis; 4. to test for the possibility of an adverse effect; 5. to modify a physiological, biochemical, or anatomical function or

abnormality; 6. to replace a missing factor; 7. to ameliorate a symptom; 8. to treat a disease; and/or 9. to induce anesthesia.

The following are notes about this definition: The term ‘medicine’, or the more old-fashioned term ‘medicament’, are acceptable synonyms for‘ medicinal product’. However, although the term ‘drug’ is often used colloquially to mean a medicinal product (as in ‘adverse drug reaction’), it is important to remember the distinction between the drug itself (the active component) and the whole product. For definitive regulatory or legislative purposes the more precise term ‘medicinal product’ is preferable the term ‘pharmaceutical product’ is sometimes used, but this excludes some biological products ‘A compound with proven biological effects’ includes chemical compounds, either drugs or pro-drugs (which themselves may have no

Glossary of terms used in Pharmacovigilance 2015

pharmacological activity), racemic mixtures, stereo isomers that may have only adverse effects, or compounds that are used for diagnostic purposes (such as contrast media used by radiologists, including ultra-sonographers). This term also includes cellular elements, such as inactivated or attenuated viruses for immunization, blood products (such as erythrocytes), viruses for gene therapy, and embryonic stem cells. That are not made pharmaceutically ‘Contaminants’ includes chemical and biological contaminants.The definition does not include food additives. The definition does not include medicinal products when they are used to probe systems, such as• use of phenylephrine to study baroreceptor reflexes. This is important, because it excludes such products from the terms of the EC Directive on Clinical Trials referred to earlier in this section.

National pharmacovigilance centers Organizations recognized by governments to represent their country in the WHO Program (usually the drug regulatory agency). A single, governmentally recognized center (or integrated system) within a country with the clinical and scientific expertise to collect, collate, analyze and give advice on all information related to drug safety.

Odds Probability of an occurrence p divided by the probability of its nonoccurrence (1 - p).

Odds ratio

Ratio of the Odds in a given population and the Odds in another population.

Omega (Ω) A measure of disproportionate reporting for drug-drug-ADR triplets in ICSR databases, designed to highlight potential signals of drug- drug interactions. Just like the more established disproportionalitymeasures for drug-ADR pairs, Ω is based on a contrast between the observed and

Glossary of terms used in Pharmacovigilance 2015

expected number of reports. A positive Ω indicates higher reporting than expected.

OTC (Over the Counter) medicine Medicinal product available to the public without prescription.

PaniFlow Software developed by UMC for collection and analysis of data in relation to vaccinations in a pandemic situation.

Periodic Safety Update Report (PSUR) Periodic Safety Update Report is a systematic review of the global safety data which became available to the manufacturer of a marketed drug during a specific time period. Produced in an internationally agreed format. PSUR should be submitted at following times (EU guidelines)

Immediately upon ad hoc request

6 monthly for the first 2 years after authorization

Annually for the subsequent 3 years

Thereafter 5 yearly

Pharmaceutical Formulation Pharmaceutical Formulation A pharmaceutical formulation, also called a ‘dos age form’, is the form in which a medicinal product is presented, for example as a tablet, capsule, elixir, solution for injection, transdermal formulation cream, or ointment. The commonly used term preparation’, is ambiguous, since it can refer to the pure substance itself (for example, as prepared from a plant) as well as the formulation When formulations are classified according to the time over which the active substance is made available to the body, two broad categories can be distinguished: immediate-release formulations and modified-release formulations. Other terms that are subsumed by the term ‘modified-release’ include sustained-release, slow-release, long-release,

Glossary of terms used in Pharmacovigilance 2015

controlled-release, timed-release, prolonged-release and delayed-release

Pharmacoepidemiology Study of the use and effects of drugs in large populations. Also see Epidemiology.

Pharmacology Study of the uses, effects and modes of action of drugs.

Pharmacovigilance The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug- related problem.

Phocomelia Characteristic deformity caused by exposure to thalidomide in the womb, also very rarely occurring spontaneously.Meaning: limbs like a seal.

Phytotherapy Western-style, scientific treatment using plant extracts or materials.

Placebo An inactive substance (often called a sugar pill) given to a group being studied to compare results with the effects of the active drug.

Polypharmacy The concomitant use of more than one drug, sometimes prescribed by different practitioners.

Glossary of terms used in Pharmacovigilance 2015

Post-marketing The stage when a drug is generally available on the market.

Predisposing factors Any aspect of the patient’s history (other than the drug) which might explain reported adverse events (genetic factors, diet, alcohol consumption, disease history, poly-pharmacy or use of herbal medicines, for example).

Pre-marketing The stage before a drug is available for prescription or sale to the public.

Prescription EventMonitoring (PEM) System created to monitor adverse drug events in a population. Prescribers are requested to report all events, regardless of whether they are suspected adverse events, for identified patients receiving a specified drug. Also more accurately named Cohort Event Monitoring.

Prescription Only Medicine (POM) Medicinal product available to the public only on prescription.

Prevalence Number of existing cases of an outcome in a defined population at a given point in time.

Prophylaxis Treatment given or action taken to prevent disease See also: Prevention or protection.

Glossary of terms used in Pharmacovigilance 2015

Rational drug use An ideal of therapeutic practice in which drugs are prescribed and used in exact accordance with the best understanding of their appropriateness for the indication and the particular patient, and of their benefit, harm effectiveness and risk. The rational use of drugs requires that patients receive medicines appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and the community (WHO 1988)

Rechallenge The point at which a drug is again given to a patient after its previous withdrawal - also see dechallenge.

Record linkage Method of assembling information contained in two or more records, eg in different sets of medical charts, and in vital records such as birth and death certificates. This makes it possible to relate significant health events that are remote from one another in time and place.

Reference risk Risk in a population of unexposed persons; also called baseline risk. Reference risk can be measured over time (incidence) or at a given time (prevalence). The unexposed population refers to a reference population, as closely comparable to the exposed population as possible, apart from the exposure.

Regulatory authority The legal authority in any country with the responsibility of regulating all matters relating to drugs.

Glossary of terms used in Pharmacovigilance 2015

Relative risk Ratio of the risk in an exposed population (absolute risk) and the risk in an unexposed population (reference risk). Relative risk is the result of a relative comparison between outcome frequencymeasurements, e.g. incidences.

Risk The probability of harm being caused; the probability (chance, odds) of an occurrence.

Serious vs. Severe Adverse Event or Reaction A serious adverse event or reaction is any untoward medical occurrence that at any dose:

results in death

requires inpatient hospitalization or prolongation of existing hospitalization

results in persistent or significant disability/incapacity

is life-threatening To ensure no confusion or misunderstanding of the difference between the terms ‘serious’ and ‘severe’, the following note of clarification is provided: The term ‘severe’ is not synonymous with serious. In the English language, ‘severe’ is used to describe the intensity (severity) of a specific event (as in mild, moderate or severe); the event itself, however, may be of relatively minor medical significance (such as severe headache). Seriousness (not severity) which is based on patient/event outcome or action criteria serves as guide for defining regulatory reporting obligations.

Glossary of terms used in Pharmacovigilance 2015

Serious adverse event or serious suspected adverse reaction An adverse event or suspected adverse reaction is considered "serious" if, in the view of either the investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.

Side effect Any unintended effect of a pharmaceutical product occurring at normal dosage which is related to the pharmacological properties of the drug.

Signal Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously.While it has been defined by the WHO as reported information on a possible causal relationship between adverse drug events of which the relationship is unknown or incompletely documented previously. It has also been defined as a set of data which constitute a hypothesis that is relevant to the rational and safe use of a drug in human. This latter definition suggests that more than one report on a particular adverse drug reaction. (ADR) is required to generate a signal depending upon the seriousness of the event and the quality of the information. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information. The

Glossary of terms used in Pharmacovigilance 2015

publication of a signal usually implies the need for some kind of review or action.

Spontaneous reporting System whereby case reports of adverse drug events are voluntarily submitted from health professionals and pharmaceutical manufacturers to the national regulatory authority. Also see ICSR.

Summary of Product Characteristics (SPC) A regulatory document attached to the marketing authorization which forms the basis of the product information made available to prescribers and patients.

Suspected Adverse Drug Reactions Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event.

Thalidomide Drug prescribed in the 1950s as a mild sleeping pill and remedy for morning-sickness for pregnant women. Led to serious birth defects and the start of modern pharmacovigilance. Returning to favour in treatment of serious diseases such as cancer and leprosy.

Time-Independent Reactions Time-independent reactions occur at any time during a course of therapy, independent of the duration of the course. They typically occur:

When the amount of drug being administered changes by a pharmaceutical mechanism (e.g. by altered availability from a pharmaceutical formulation);

When the concentration of the drug at the site of action changes by a pharmacokinetic mechanism(e.g. digoxin toxicity when renal function worsens)

Glossary of terms used in Pharmacovigilance 2015

When the pharmacological response is altered by a pharmacodynamic mechanism without a change in concentration at the site of action (e.g. digoxin toxicity in association with potassium depletion)

When such a reaction occurs, the delay before it occurs may be affected by the pharmacokinetics of the drug, but that is not an

aspect of its time dependency as it is defined here

Time-Dependent Reactions Time-dependent reactions are of six subtypes 1) rapid, 2) first dose, 3) early, 4) intermediate, 5) late, and 6) delayed. 1) Rapid reactions:

Rapid reactions occur when a drug is administered too rapidly, for example the red - man syndrome with vancomycin. They are typically toxic reactions

2) First-dose reactions:

First-dose reactions occur after the first dose of a course of treatment and not necessarily thereafter. They are typically hyper-susceptibility reactions. Examples include hypotension after the first dose of an ACE inhibitor and type I allergic reactions. In the latter, the reaction is observed after the first dose of a course; whether or not there has been a record of previous exposure 30% of those who develop anaphylaxis with penicillin have no such record. We regard a previous sensitizing exposure as causing a change in susceptibility.

3) Early reactions:

Early reactions occur early in treatment then abate with continuing treatment. They are typically collateral effects. These are reactions to which patients develop tolerance (e.g. nitrate-induced headache).

Glossary of terms used in Pharmacovigilance 2015

4) Intermediate reactions: Intermediate reactions occur after some delay; however, during longer term therapy the risk falls. If after a certain time there is no reaction, there is little or no risk that it will occur later. They can be collateral or hypersusceptibility reactions. Examples are allergic reactions of type II (e.g. thrombocytopenia due to quinine), type III (e.g. interstitial nephritis with penicillin), and type IV (e.g. cutaneous allergy due to antihistamines), and the ampicillin/amoxicillin pseudo allergic rash. Non-allergic reactions of this type include the increased risk of neutropenia with carbimazole, and of venous thromboembolism with antipsychotic drugs. We believe that intermediate reactions occur in populations of individu-als with different susceptibilities. Those at high risk have the reaction and stop taking the drug. Those at low risk do not have the reaction and can be regarded as ‘healthy survivors’. Thus, the population risk appears to fall with time.

5) Late reactions (including withdrawal reactions):

Late reactions occur rarely or not at all at first, but the risk increases with continued or repeated exposure. They are typically collateral effects. Examples include many of the adverse effects of glucocorticoids and tardive dyskinesia with dopamine receptor antagonists. Withdrawal reactions are late reactions that occur when, after prolonged treatment, a drug is withdrawn or its effective dose is reduced.

Traditional medicines Traditional medicine is the sum total of the knowledge, skills, and practices based on the theories, beliefs, and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health as well as in the prevention, diagnosis, improvement or treatment of physical and mental illness. Also see Allopathic medicine.

Glossary of terms used in Pharmacovigilance 2015

Unexpected adverse reaction An adverse reaction, the nature or severity of which is not consistent with domestic labeling or market authorization, or expected from characteristics of the drug.

VigiBase The name of the WHO Global ICSR Database.

VigiFlow VigiFlow is a complete ICSR management system created and maintained by the UMC. It is web-based and built to adhere to the ICH-E2B standard. It can be used as the national database for countries in the WHO Program as it incorporates tools for report analysis, and facilitates sending reports to VigiBase.

Vigimed Share-point based conferencing facility, exclusive to member countries of the WHO Program for International Drug Monitoring for fast communication of topical pharmacovigilance issues.

VigiMine A statistical tool within VigiSearch with vast statistical material calculated for all Drug-ADR pairs (combinations) available in VigiBase. The main features include the disproportionality measure (IC value) stratified in different ways and useful filter capabilities.

VigiSearch A search service for accessing ICSRs stored in the VigiBase database offered by the UMC to national pharmacovigilance centers and other third-party inquirers.

WHO-ART Terminology for coding clinical information in relation to drug therapy.WHO-ART is maintained by UMC.

Glossary of terms used in Pharmacovigilance 2015

WHO Drug Dictionary (WHO DD) The WHO Drug Dictionary is an international classification of drugs providing proprietary and on-proprietary names of medicinal products used in different countries, together with all active ingredients. Or WHO DD is a dictionary of known medicines maintained by the World Health Organization since 1968. The dictionary also associates a drug with an Anatomical-Therapeutic Chemical (ATC) Classification; that is, the parts and systems of the human body where this drug might have an effect. The WHO-DD dictionary is used to code medications, classify these into ATC categories, and identify the active ingredients associated with each medication. Recent developments have added extra data to create two extended versions of the Dictionary: WHO Drug Dictionary Enhanced and WHO Herbal Dictionary. WHO-DD: ATC Coding System Anatomical - Therapeutic Chemical Classification Contains 5 Levels

1st level has 14 Anatomical main groups

2nd level has one therapeutic main group, consists of two digits

3rd and 4th levels are chemical /pharmacological/ therapeutic subgroups, consists of one letter each

5th level represents the chemical substance, consists of two digits

ATC Coding Example: ATC code A10BA02 is used here for illustration A-1st level, Anatomical main group (Alimentary tract and metabolism) A10-2nd level, Therapeutic subgroup (Drugs used in diabetes) A10B-3rd level, Pharmacological subgroup (Oral blood glucose lowering drugs) A10BA-4th level, Chemical subgroup (Biguanides) A10BA02-5th level, Chemical substance (Metformin)

Benefit risk Whereas risk is defined as the probability that harm will be caused by the drug, benefit is defined as the therapeutic good which the drug offers. Harm refers to the nature and extent of the actual damage which the drug could cause. To make careful risk/effectiveness balance

Glossary of terms used in Pharmacovigilance 2015

assessments, there is need to know what types of harms and benefits a product can produce and how likely such harms and benefits are to occur. Risk/benefit analysis is an important aspect of pharmacoviligilance signal detection process. This is because as stated in the preamble, there is no such thing as a safe drug (Paracelsius‘principle). Indeed the rule of the thumb in pharmacology is that no drug has a single action. Aside from the therapeutic benefits of the drug, there are associated adverse effects. The drug is said to be effective if it is beneficial under real world circumstances and not under the ideal circumstances which are created during clinical trials. In real world conditions, there may be co-morbid situations and lack of compliance with dosage regimen. These problems are not expected to be present during clinical trials when the the term efficacy seems more appropriate. It should be noted that the term benefit like risk is largely subjective and can be assessed differently by different people. Risks are expressed as a percentage of the population. In evaluating the clinical benefit of a drug, consideration should be given to evidence which is best given by the patient himself although the opinions of clinicians and other care givers also count. Therefore, total quality of life rather than the use of surrogate markers should be encouraged. Quality is ―the consistent and reliable performance of services or products in conformity with specified standards. Pharmacovigilance is a quality assurance process that forms an integral part of the patients‘care. It aims at getting the best outcome of treatment with medicines.

Glossary of terms used in Pharmacovigilance 2015

References:

1. http://www.who.int/selection medicines/en/

2. who-umc.org/Graphics/24729.pdf

3. Leape, Lucien. Error in Medicine. Journal of the American

Medical Association 272(23):1851-57 (Dec. 21, 1994).

4. Volume 9 of the Rules Governing Medicinal Products for Human

and Veterinary Use in the European Union

5. Title 21--Food and Drugs, Chapter I--Food and Drug

Administration, Department of Health and Human Services,

Subchapter D--Drugs For Human Use, PART 312 --

investigational new drug application

6. ‘‘GHAIN Project, Pharmacovigilance for Antiretroviral Drugs

Training for Health Care Professionals Participant’s Manual,

April 2009’’.

7. Dorland’s Illustrated Medical Dictionary

Glossary of terms used in Pharmacovigilance 2015

This glossary is made possible by the generous support of the American people

through the U.S. Agency for International Development (USAID), under the

terms of Associate Award Cooperative Agreement Number 306-A-00-11-

00532-00 with Management Sciences for Health (MSH) under Leader Award

Number GHN-A-00-07-00002-00. The contents are the responsibility of

Management Sciences for Health and do not necessarily reflect the views of

USAID or the United States Government.

About SPS

The Strengthening Pharmaceutical Systems (SPS) Program strives to build

capacity within developing countries to manage all aspects of pharmaceutical

systems and services effectively. SPS focuses on improving governance in the

pharmaceutical sector, strengthening pharmaceutical management systems and

financing mechanisms, containing antimicrobial resistance and enhancing

access and appropriate use of medicines.