- Adverse Event (AE)
- Adverse Event of Special Interest (AESI)
- Adverse Drug Reaction (ADR)
- Aggregate reports
- Benefit-risk assessments
- Benefit-risk balance
- Case reports
- Company Core Safety
- Company Core Data Sheet
- Council for International Organizations of Medical Sciences (CIOMS)
- Clinical development program
- Clinical trial
- Critical terms
- Causal relationship
- Data Monitoring Committee
- Development core safety information (DCSI)
- Development pharmacovigilance and risk management plan
- Disproportionality analysis
- Designated Medical Event (DME)
- Drug Abuse
- European Medicines Agency (EMA)
- EudraVigilance Medicinal Product Dictionary (EVMPD)
- Expected adverse drug reaction
- Expedited Reporting
- Frequency of ADRs
- Good pharmacovigilance practice
- Important medical event (IME)
- Unlabeled (or labelled)
- Marketing Authorization Holder (MAH)
- Medication error
- Medical Dictionary for Regulatory Activities (MedDRA)
- Minimum criteria for reporting
- Missing information
- National pharmacovigilance centers or National Competent Authority (NCA)
- Number needed to harm (NNH)
- Odds and Odds Ratio
- Off-label use or Misuse
- Post-authorization safety study (PASS)
- Pharmacovigilance Master File
- Pharmacovigilance system
- Postmarketing surveillance
- Predisposing factors
- Prescription event monitoring (PEM)
- Rational drug use
- Reference risk (or baseline risk)
- Risk management
- Risk Management Plan (RMP)
- Risk minimization activity
- Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR)
- International Serious Adverse Events Consortium (SAEC)
- Safety concern
- Safety specification
- Signal management process
- Signal validation
- Solicited reports
- Summary of product characteristics (SmPC)
- Spontaneous reporting
- Suspected unexpected serious adverse reaction (SUSAR)
- Temporal relationship
- Type (A to F) of adverse drug reaction
- Unexpected adverse drug reaction
- United States Prescribing Information (USPI)
- WHOART (WHO Adverse Reactions Terminology)
- WHO DD (WHO Drug Dictionary)
Adverse Event (AE)
Any untoward medical occurrence that happens during treatment with a medical product, whether or not it has a causal relationship with this treatment. Note: Side effect” is a lay-man’s term for Adverse Event and should not be used in pharmacovigilance.
Adverse Event of Special Interest (AESI)
A noteworthy event for a product or class of products that a sponsor wants to monitor carefully. It can be serious or non-serious, or it be potential precursor or prodrome for more serious medical conditions in susceptible individuals. It should be described in protocols and instructions provided for investigators as to 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 noxious 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.
Reports of a set of cases, 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 for regulators of all pertinent safety information collected during the reporting period related to a drug, biologic or vaccine under development, whether or not 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 assessment of the worldwide safety, 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.
Events linked via one or multiple factors (i.e. chronology) but not necessarily having a cause and effect relationship.
An estimated gain for an individual or a population.
Analysis of the favorable (beneficial) and unfavorable 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.
Individual reports of the experience of single patients, or patients managed as group. At minimum, an adverse event case report must have a reporter, product, patient, and event. Individual Case Safety/Study Report (ICSR) – synonym: Adverse (drug) reaction report. Reporting of suspected adverse reaction to a medicinal product that occurs in an individual patient.
Method for assigning probability to the likelihood of a causal relationship between an AE and a suspected drug; according to established algorithms.
Company Core Safety Information (CCSI)
All safety information contained in the core data sheet prepared by the medicinal product MAH and which the MAH requires to be listed in all countries where the company markets the product.
Company Core Data Sheet (CCDS)
Document prepared by the MAH containing the medicinal product’s:
- Safety information
- Indications, dosing
- Pharmacology and other information concerning the product.
Council for International Organizations of Medical Sciences (CIOMS)
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)
Clinical development program
Refers to all clinical trials 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” in WHOART refer to or might indicate serious disease states and warrant special attention.
- 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
(synonyms: Independent Data Monitoring Committee, Data and Safety Monitoring Board) This committee is established by the sponsor to:
- Assess the progress of a clinical trial, the safety data, and the critical efficacy endpoints
- Recommend to the sponsor whether to continue, modify, or stop a trial
Dechallenge is the 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)
Rechallenge means reintroducing the drug to the patient. A positive rechallenge (the AE reappears) strongly suggests a causal relationship.
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.
Screening of ICSR databases for statistical associations between products and events whereby the observed frequency is different than the expected frequency. For ADRs caused by one drug (called drug-event pairs), common measures of disproportionality are:
- 1. Frequentist statistics
- PRR (Proportional Reporting Ratio)
- ROR (Reporting Odds Ratio)
- 2. Bayesian statistics
- o IC (Information Component)
- o EGBM (Empirical Bayes Geometrical Mean).
For ADRs caused by the interaction of two drugs (called drug-drug-event triplets), the Omega (Ω) measure of disproportionality can be used.
Designated Medical Event (DME)
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.
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.
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
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.
The EMA’s system to support the electronic exchange, management, and evaluation of ICSRs related to all medicinal products authorized in the European Economic Area (EEA). Companies and Member States report reactions directly to Eudravigilance. The Eudravigilance database is partially open to healthcare professionals and the public. Eudravigilance reports database: www.adrreports.eu
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.
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
The EMA has issued these guidelines for the conduct of pharmacovigilance in the EU for human medical products.
The nature and extent of actual damage that can be caused by a drug. Damage is measured by frequency of occurrence, severity or duration
The inherent capability of an intervention to cause harm.
International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals.
Important medical event (IME)
The rate of new cases of an outcome occurring per number of known at risk or exposed; and is a measurement of risk.
Unlabeled (or labelled)
Any reaction not mentioned in the official approved product information is unlabeled (otherwise it is termed labelled).
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.
Any mistake in the way a medication is taken or administered (prescription, storage, dispensing, preparation, administration…), that has the potential to harm the patient. Medication errors are outside the use prescribed by the marketing authorization but can lead to ADRs.
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
An identifiable reporter, patient, event and a suspect medicinal product are required for reporting cases of suspected adverse events.
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.
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)
Number of individuals needed to be treated for some specified period in order that one person would have one harmful event.
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.
Administration of a quantity of a medicinal product above the maximum recommended dose allowed by the authorized product information.
Post-authorization safety study (PASS)
Study relating to an authorized medicinal product conducted with the aim of studying a safety hazard, confirming the safety profile of the product, or evaluating risk management measures.
The study of the use and effects of drugs in large numbers of people using an epidemiological approach
Study of the uses, effects and modes of action of drugs.
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 Master File
A compilation of information, maintained by the MAH. containing a detailed description of the pharmacovigilance system they use, available to competent authorities upon request.
A system used by an organization to comply with pharmacovigilance regulations and designed to monitor the safety of authorized medicinal products.
The study of drug use and effects after release into the market.
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).
The proportion of total cases in a population at a particular time and a descriptive statistic, rather than a measurement of risk.
Qualified Person responsible for Pharmacovigilance
Rational drug use
Therapeutic practice where drugs are prescribed and used appropriately for the indication and the patient’s specific characteristics.
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).
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
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
- Product information
- Healthcare professional communications / educational materials/li>
- Patient communications / educational materials/li>
- results in death
- requires patient hospitalization
- results in persistent or significant disability or incapacity
- is life-threatening
- or is a congenital anomaly/birth defect.
- “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
- The important identified risks
- Important potential risks
- Missing information
- 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
- Signal detection
- Signal analysis and prioritization
- Signal validation
- Signal evalutaion
- Recommendation for action
- 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
- 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)
- Positive (event occurring during the use of the drug or within a plausible range based on its half-life)
- 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.
- 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.
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:
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR)
Any untoward medical occurrence that at any dose:
In addition, medical judgment should be used to assess an AE as serious due to its medical importance: refer to MedDRA’s IME (important medical event) terms list. Remark: “severe” is not synonymous with “serious”:
International Serious Adverse Events Consortium (SAEC)
Non-profit consortium formed between the US FDA, industry, academia and the Wellcome Trust to identify genetic variants associated with SAEs.
It should also address:
Reported information on a new possible causal relationship (or a new aspect of a known relationship) between an adverse event and a drug. A signal is considered important and warrants further investigation. 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:
Evaluation of the data supporting a detected signal to verify that there is sufficient evidence demonstrating a new potentially causal association, or a new aspect of a known association.
Reports derived from organized data collection systems, including:
Summary of product characteristics (SmPC)
This legal document is approved as part of the marketing authorization of a medicinal product in the EU and updated as new data emerge. It is the basis of information for healthcare professionals on how to use the medicinal product safely and effectively (therapeutic indication, dosage, how to administrate, contraindications, precautions for use, etc.). The equivalent for the USA is called USPI.
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:
Suspected unexpected serious adverse reaction (SUSAR)
An ADR which is both unexpected and serious.
It is assessed based on drug kinetics, toxicity mechanisms, involved organ, and the physiopathology of the event. Categories are:
Type (A to F) of adverse drug reaction
Unexpected adverse drug reaction
An adverse reaction whose nature, severity, specificity, or outcome is not consistent with the description given in 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 and 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:
World Health Organization
WHOART (WHO Adverse Reactions Terminology)
Dictionary meant for rational coding of adverse reaction terms, 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.