PV Glossary
Adverse Event of Special Interest (AESI)
An event for a product that a sponsor wants to monitor. It can be serious or non-serious. In Clinical studies it should be described in protocols and instructions provided for investigators how and when to report it to the sponsor.
Adverse Drug Reaction (ADR)
An adverse event where the drug treatment is considered having a possible causal relationship with the aggregate unintended medical occurrence. An adverse drug reaction is considered as a possible response to the treatment. The word “reaction” implies this possibility of a causal relationship.
Aggregate reports
Reports of a set of cases, an overview and assessment meant for regulatory authorities.
- Annual Safety Report (ASR): In clinical trials, an annual report of all newly available safety information. An ASR includes a global analysis for all trials with the same Investigational Medicinal Product (IMP).
- Development Safety Update Report (DSUR): Annual review and evaluation by the sponsor of safety information collected during the reporting period related to a drug, biologic or vaccine under development, whether it is marketed.
- Periodic Safety Update Report (PSUR): Also called PBRER (Periodic Benefit Risk Evaluation Report). This report (internationally agreed format) provides a periodic comprehensive evaluation of the risk-benefit balance, efficacy and effectiveness data of a marketed drug or biological product. It contains a summary of relevant data, a scientific evaluation, and data concerning sales volume, prescription, and population exposure.
- Periodic adverse drug experience report (PADER): A post-marketing safety report submitted to the United States Food and Drug Administration (USFDA). The main objective is to provide summary data and an assessment of an approved drug product’s benefit risk profile from the post marketing exposure.
Association
Events linked via one or multiple factors (i.e. chronology) but not necessarily having a cause and effect relationship.
Benefit
An estimated gain for an individual or a population.
Benefit-risk assessments
Analysis of the beneficial and unbeneficial results of doing specific actions. Also called “benefit-harm” or “effectiveness-risk” analysis.
Benefit-risk balance (or effectiveness/risk)
An evaluation of the positive therapeutic effects of the medicinal product in relation to the risks (quality, safety, or efficacy) of the medicinal product for the patients’ or public health.
Pharmacovigilance activities and PSURs / DSURs help to continuously evaluate this balance, and quantitatively assess the merit of a medicinal product comparatively to other therapies – using more comprehensive data than pre-marketing information that is based on a limited number of selected patients.
Case reports/ Individual Case Safety/Study Report (ICSR)
A safety report which includes information required for reporting the adverse events and problems related to a medicinal product that occurs in an individual patient.
At minimum, an adverse event case report must have a reporter, product, patient, and event.
Causality assessment
Method for assigning probability to the likelihood of a causal relationship between a suspected drug and a drug reaction.
CIOMS- Council for International Organizations of Medical Sciences
The CIOMS is a body set up under WHO and UNESCO. It has developed the following pharmacovigilance guidelines:
- I – International reporting form
- II – Periodic safety update reports (PSUR)
- III – Core data sheets (CCDS…)
- IV – Benefit-risk assessments
- V – Practical issues in pharmacovigilance
- VI – Clinical trial safety data
- VII – Development safety update reports (DSUR)
Company Core Safety Information (CCSI)
All safety information contained in the core data sheet prepared by the Marketing Authorisation Holder (MAH) and which the MAH requires to be listed in all countries where the company markets the product.
Company Core Data Sheet (CCDS)
A company core labeling document is an internal Regulatory document that serves as the company’s global reference document for a product containing:
- Safety information
- Indications, dosing
- Pharmacology and other information concerning the product.
Clinical development program
Refers to the clinical development activities being conducted with the same investigational drug.
Clinical trial, clinical study
Systematic study of an investigational medicinal product on human subjects designed to:
- Discover or verify its clinical or pharmacological effects
- Identify its adverse reactions
- Study its absorption, distribution, metabolism and excretion in order to evaluate its safety or efficacy
Critical terms
“Critical Terms” in WHOART is a subset of adverse reaction terms referring to, or possibly being indicative of, serious disease states, which have been regarded as particularly important to follow up. If a Preferred term is indicated as a Critical Term, its linked Included terms are also regarded as Critical Terms.
Causal relationship
- certain– sufficient information provided to determine that no other reasonable explanation exists, occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals.
- (A) probable, likely – sufficient information provided to no other equally plausible explanation exists,
- (B) possible – information provided supports a reasonable time sequence to administrations of the drug, but which could also be explained by another equally possible explanation (i.e. concurrent disease or other drugs or chemicals). Information on drug withdrawal may be lacking or unclear.
- (O1) conditional, unclassified – a clinical event, including laboratory test abnormality, reported as an adverse reaction, about which more data is essential for a proper assessment, or the additional data is under examination.
- (O) unassessable, unclassifiable – a report suggesting an adverse reaction which cannot be judged because information is insufficient or contradictory, and which cannot be supplemented or verified.
- (N) unlikely – a clinical event, including laboratory test abnormality, with a temporal relationship to drug administration which makes a causal relationship improbable, and in which other drugs, chemicals or underlying disease provide plausible explanations
It is determined based on:
- Temporal relationship, drug’s half-life
- Pathological mechanisms
- Alternative explanations for the event
- Dechallenge and rechallenge
- Concomitant diseases or use of other medicines
- Previous experience with the drug…
Data Monitoring Committee
A data monitoring committee (DMC) – sometimes called a data and safety monitoring board (DSMB) – is an independent group of experts who monitor patient safety and treatment efficacy data while a clinical trial is ongoing.
Dechallenge
Dechallenge is a response observed for the reduction or disappearance of adverse drug reactions (ADR) on withdrawal of a drug from a patient to observe:
- The continuity of an AE (negative dechallenge – causal relationship less likely)
- The reduction or disappearance of an AE (positive dechallenge – causal relationship more likely)
Development core safety information (DCSI)
This section of an Investigator’s Brochure (IB) is identical in structure to the CCSI and contains a summary of all relevant safety information (described in more detail in the rest of the IB).
Development pharmacovigilance and risk management plan
Plan to conduct the detection, assessment, understanding, reporting and prevention of AEs of medicinal products during clinical trials.
Disproportionality analysis
Disproportionality analysis is primarily a tool to generate hypotheses on possible causal relations between drugs and adverse effects, to be followed up by clinical assessment of the underlying individual case reports.
DME (Designated Medical Event)
Serious and rare medical event that is often causally associated with drugs across multiple pharmacological / therapeutic classes. Even small number of reports of such event can trigger a signal and require special attention. The EMA maintains a list of MedDRA Preferred Terms that identifies DMEs.
Drug Abuse
Intentional off-label use of a medicinal product. Although the drug is not being used according to the marketing authorization or physician’s recommendation, abuse can result in ADRs.
Efficacy
The ability of a drug to produce the intended effect (scientific evaluation).
European Medicines Agency (EMA)
The European Union’s organization aimed at protecting and promoting public health, including the responsibility of evaluating and supervising medical products. The EMA includes the following committees and groups:
- CHMP (Committee for Medicinal Products for Human Use): prepares the EMA’s opinion on all questions related to medicines for human use.
- CMDh (Coordination Group for Mutual Recognition and Decentralized Procedures, human): examines cases of disagreement between Member States related to marketing authorization and promotes harmonization of marketing authorizations in the EU.
- PRAC (Pharmacovigilance Risk Assessment Committee): advises the CMDh and the CHMP on the assessment of pharmacovigilance data after the medicinal product’s authorization
EUDRAGENE
European collaboration that established a collection of DNA samples for studying genes which influence SARs or ADRs, for the purpose of a better understanding of adverse drug reactions.
EudraVigilance
The EMA’s system for managing and analysing information on suspected adverse reactions to medicines which have been authorised or being studied in clinical trials in the European Economic Area (EEA). The European Medicines Agency (EMA) operates the system on behalf of the European Union (EU) medicines regulatory network.
EudraVigilance Medicinal Product Dictionary (EVMPD)
EMA’s central product database, populated by data from marketing authorization holders for all products authorized in the EU as well as those in development, to assist the pharmacovigilance activities in the EU.
Expected adverse drug reaction
ADR consistent with the reference safety information (Investigator’s brochure for an investigational product, summary of product characteristics) for an approved product.
Expedited Reporting
Rapid submission of an ICSR to the Regulatory Authorities in compliance with the legislation and local regulatory guidelines.
Frequency of ADRs
The following are standard ADR frequency categories where the denominator must be defined to provide context:
- Very common: > 10%
- Common: [1%, 10%]
- Uncommon: [0.1%, 1%]
- Rare: [0.01%, 0.1%]
- Very rare: <0.01%
Good pharmacovigilance practice (GDP)
The EMA has issued these guidelines for the conduct of pharmacovigilance in the EU for human medical products.
Harm
The nature and extent of actual damage that can be caused by a drug. Damage is measured by frequency of occurrence, severity or duration.
Hazard
The inherent capability of an intervention to cause harm.
ICH
International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals.
Important medical event (IME)
MedDRA includes a term list of important medical events (available on the EMA website), which aims to facilitate the classification of suspected ADRs, data analysis and the assessment of ICSRs.
Incidence
The rate of new cases of an outcome occurring per number of known at risk or exposed; and is a measurement of risk.
Insife
Innovation, insights and solutions for Life Sciences.
International Serious Adverse Events Consortium (iSAEC)
A nonprofit organization that coordinates and funds efforts to identify genetic factors that confer a risk for serious, drug-induced adverse events.
Marketing Authorization Holder (MAH)
The marketing authorization holder of a medicinal product is the pharmaceutical company that has filed and obtained the marketing authorization submissions for the product.
Medication error
Defined as “any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient, or consumer,” according to the National Coordinating Council for Medication Error Reporting and Prevention.
Medical Dictionary for Regulatory Activities (MedDRA)
International medical terminology standard used by regulatory authorities and the biopharmaceutical industry through the entire regulatory process, from pre-marketing to post-marketing.
Minimum criteria for reporting
The minimal dataset required to consider information as a reportable AE:
- An identifiable reporter
- patient
- event
- suspect medicinal product.
Missing information
Potentially clinically significant gap in knowledge about the safety of a medicinal product for a specific patient population or concerning certain anticipated utilization (for instance long term use). Typical examples are children, pregnant or lactating women… Missing information is identified and monitored in the RMP and the PSUR.
National pharmacovigilance centers or National Competent Authority (NCA)
Regulatory authority within a country with the clinical and scientific expertise to collect, analyze and advise on drug safety. The national competent authorities are primarily responsible for the authorisation of medicines available in the EU that do not pass through the centralised procedure.
Near-misses
Medication errors with high potential for causing harm but did not (cancelled before reaching a patient or reaching the patient but who did not have untoward consequences).
Number needed to harm (NNH)
The number needed to harm (NNH) is a derived statistic that tells us how many patients must receive a particular treatment for 1 additional patient to experience a particular adverse outcome.
Odds and Odds Ratio
An Odds is the probability of an occurrence divided by the probability of its non-occurrence. The Odds ratio is the ratio of the Odds between two populations.
Off-label use or Misuse
Situations where a medicinal product is intentionally used for a medical purpose not in accordance with the marketing authorization. For instance, medicine used:
- For disease that it is not approved to treat
- Through different route or method of administration
- With different dose
- In different group of patients
They are not medication errors, as they are intentional.
Overdose
Administration of a quantity of a medicinal product above the maximum recommended dose allowed by the authorized product information.
Post-authorization safety study (PASS)
A post-authorisation safety study is a study that is conducted after a medicine has been authorised to obtain further information on a medicine’s safety, or to measure the effectiveness of risk-management measures. The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for assessing the protocols of imposed PASS and for assessing their results.
Pharmacoepidemiology
The study of the use and effects of drugs in large numbers of people using an epidemiological approach.
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, in order to:
- Prevent harm from ADRs in humans arising from the use of authorized medicinal products
- Promote the safe and effective use of medicinal products, through providing timely information about the safety of medicinal products
Pharmacovigilance also concerns herbals, traditional and complementary medicines, blood products, biologicals, medical devices, vaccines.
Pharmacovigilance System Master File (PSMF)
A compilation of information, maintained by the MAH. containing a detailed description of the pharmacovigilance system they use, available to competent authorities upon request.
Pharmacovigilance system
A system used by an organization to comply with pharmacovigilance regulations and designed to monitor the safety of authorized medicinal products.
Postmarketing surveillance
The study of drug use and effects after release into the market.
Predisposing factors
Aspects of the patient’s history which might explain reported adverse events (genetic, other drugs, disease history…).
Prescription event monitoring (PEM)
System created to monitor adverse drug events for identified patients receiving a specified drug (prescribers are requested to report all events, suspected adverse or not).
Prevalence
The proportion of total cases in a population at a particular time and a descriptive statistic, rather than a measurement of risk.
QPPV
Qualified Person responsible for Pharmacovigilance.
Rational drug use (RDU)
Rational drug use is the process of appropriate prescribing, dispensing, and patient use of drugs for diagnosis, prevention, and treatment of diseases.
Rechallenge
This refers to the restarting of the same drug after having stopped it, usually for an AE. A positive rechallenge (the AE reappears) strongly suggests a causal relationship.
Reference risk (or baseline risk)
Risk in a population of unexposed persons. It can be measured over time (incidence) or at a given time (prevalence).
Risk
The probability of developing an outcome (refers normally but not always to a negative outcome).
- Absolute risk or Incidence Rate: The observed or calculated probability of the occurrence of an event in a population, without context. (e.g. 1 event in 100).
- Relative risk: Ratio of the risk in an exposed population (absolute risk) and an unexposed population (reference risk).
- Attributable risk (or excess risk): Difference between the risk in an exposed population (absolute risk) and the risk in an unexposed population (reference risk).
- Potential risk: An untoward occurrence for which the medicinal product can be suspected but where this association has not been confirmed, for instance:
- Pre-clinical safety concerns that have not been observed in clinical studies
- AEs observed but with a comparative effect (with placebo) not large enough to suggest a causal relationship
- Event known to be associated with other products of the same class
- Identified risk: Untoward occurrence for which there is evidence of an association with the medicinal product (usually been described in the SmPC). For instance, ADRs:
- Demonstrated in nonclinical studies and confirmed by clinical data
- Observed in clinical trials or epidemiological studies for which the magnitude of the effect suggests a causal relationship
- Suggested by spontaneous reports where causality is strongly supported by temporal relationship and biological plausibility
- Important risk: A risk that could impact the risk-benefit profile of the product or have implications for public health. Any risk that could be included in the contraindications / precautions section of the product labelling should be considered important. Important risks are identified, characterized, and monitored in the DSUR, the RMP and the PSUR. An important identified risk usually warrants:
- Evaluation in the pharmacovigilance plan of frequency, severity, seriousness, outcome under normal conditions of use, populations particularly at risk…
- Risk minimization activities: product information for instance
Risk management
Activity that aims to ensure that the benefits of a medicinal product exceed the risks by the greatest achievable margin, by increasing the benefits or reducing the risks in three stages:
- Characterization of the safety profile of the medicinal product
- Planning of pharmacovigilance activities to identify and characterize risks
- Risk minimization and mitigation, assessment of the effectiveness of these activities
- The set of risk management activities and interventions is called the Risk management System.
Risk Management Plan (RMP)
MAHs must prepare an RMP (Risk Management Plan) to implement the risk management system.
Risk minimization activity
Intervention intended to reduce the probability of the occurrence of an ADR or to reduce its severity, for instance:
- Product information
- Healthcare professional communications / educational materials
- Patient communications / educational materials
Safety
Safety concern
Safety specification
- The important identified risks
- Important potential risks
- Missing information
It should also address:
- Populations potentially at risk (where the product is likely to be used in labelled and off-labelled use)
- Safety questions which warrant further investigation during the post-authorization period
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR)
Any untoward medical occurrence that at any dose:
- results in death
- requires patient hospitalization
- results in persistent or significant disability or incapacity
- is life-threatening
- or is a congenital anomaly/birth defect.
In addition, medical judgment should be used to assess an AE as serious due to its medical importance: refer to MedDRA IME (important medical event) terms list. Remark: “severe” is not synonymous with “serious”:
- “Severe” describes the intensity of an event (mild, moderate or severe), the event itself may be of minor medical significance (severe headache) and therefore not “serious”
- “Serious” describes the potential outcome for the patient and is used to define regulatory reporting obligations
Signal
Refers to information on a new or known side effect that may be caused by a drug and is typically generated from more than a single report of a suspected side effect. It’s important to note that a signal does not indicate a direct causal relationship between a side effect and a medicine, but is essentially only a hypothesis that, together with data and arguments, justifies the need for further assessment.
Signals are continuously monitored, evaluated and presented in the PSUR by pharmaceutical companies.
Signal management process
A set of activities performed to determine whether there are signals associated with medicinal product (based on ICSRs, data from active surveillance systems or studies, literature information, etc.) including:
- Signal detection
- Signal analysis and prioritization
- Signal validation
- Signal evalutaion
- Recommendation for action
Signal validation
Process of evaluating the data supporting a detected signal in order to verify that the available documentation contains sufficient evidence demonstrating the existence of a new potentially causal association, or a new aspect of a known association, and therefore justifies further analysis of the signal.
Solicited reports
Reports derived from organized data collection systems, including:
- Clinical trials
- Clinical registries
- Post-approval patient use programs
- Patient support programs
- Patient disease management programs
- Surveys of patients or healthcare providers
- Information on efficacy or patient compliance
Summary of product characteristics (SmPC)
An EMA required document describing the properties and the officially approved conditions of use of a medicine. Summaries of product characteristics form the basis of information for healthcare professionals on how to use the medicine safely and effectively.
The equivalent for the USA is called USPI.
Spontaneous reporting
Reporting of AE cases by health professionals and pharmaceutical companies which does not derive from a study or any organized data collection scheme (i.e. is not solicited). Stimulated reporting Reporting of an AE case triggered by a specific occurrence such as:
- A direct healthcare professional communication (DHPC)
- A publication in the press
- Survey of healthcare professionals by company representatives
- Invitation from patient organizations to their members
- Reporting made during early phase post-marketing vigilance (EPPV)
Suspected unexpected serious adverse reaction (SUSAR)
An ADR which is both unexpected and serious.
Temporal relationship
It is assessed based on drug kinetics, toxicity mechanisms, involved organ, and the physiopathology of the event. Categories are:
- Positive (event occurring during the use of the drug or within a plausible range based on its half-life)
- suggestive
- compatible
- weak
- negative
Type (A to F) of adverse drug reaction
- A (augmented): common dose-related reaction, related to a pharmacological action of the drug, predictable and with low mortality.
- B (bizarre): uncommon non-dose-related reaction, not related to a pharmacological action of the drug, unpredictable and with high mortality.
- C (chronic): uncommon dose- and time-related reaction related to the cumulative dose.
- D (delayed): uncommon reaction occurring sometime after the use of the drug, usually dose-related.
- E (end of use): uncommon reaction that occurs soon after withdrawal of the drug.
- F (failure): common dose-related unexpected failure of therapy reaction, often caused by drug interactions.
Unexpected adverse drug reaction
An adverse reaction whose nature, severity, specificity, or outcome is not consistent with the applicable product labelling or market authorization (USPI in the US, SmPC in Europe).
United States Prescribing Information (USPI)
It sets out the agreed usage of the drug in the USA. It provides information for healthcare professionals on the drug’s usage, efficiency and safety. This is part if the drug’s marketing authorization in the USA. The equivalent in the EU is called the SmPC. Urgent union procedure In case of a serious concern concerning a medicinal product:
- The European Commission or a Member State trigger this alert procedure
- The EMA announces the procedure and gives supporting information
- The European Commission can ask Member States to take temporary urgent measures.
Unlabelled (or labelled)
Any reaction not mentioned in the official approved product information is unlabelled (otherwise it is termed labelled).
Vigibase
WHO
World Health Organization
WHOART (WHO Adverse Reactions Terminology)
A dictionary meant to serve as a basis for rational coding of adverse reaction terms. The system is maintained by the Uppsala Monitoring Centre (UMC), the World Health Organization Collaborating Centre for International Drug Monitoring.
WHO DD (WHO Drug Dictionary)
An international classification of drugs providing the names and active ingredient of medicinal products used in different countries.
