Annual Safety Report

A periodic safety report submitted annually during the clinical development phase of a medicinal product, summarising the cumulative safety data collected over the reporting period. The ASR is required for investigational medicinal products under clinical trial authorisations in the EU and is distinct from the DSUR, though the two are closely related. It provides a risk-benefit assessment to support ongoing trial conduct.

GVP Module VII (P-II), EU CTR 536/2014

Biologics License Application

The regulatory submission required by the FDA to obtain approval to market a biological product in the United States. A BLA must demonstrate the safety, purity, and potency of the biologic and is reviewed under the Public Health Service Act rather than the Federal Food, Drug, and Cosmetic Act. Pharmacovigilance commitments, including post-marketing surveillance plans, are a key component of BLA approval.

21 CFR Part 601, PHSA §351

Adverse Drug Reaction Causality Assessment

The systematic evaluation of the likelihood that a suspected medicinal product caused an observed adverse event, taking into account factors such as temporal relationship, dechallenge/rechallenge results, plausibility, and alternative explanations. Regulatory agencies and MAHs use standardised tools such as the WHO-UMC causality categories (certain, probable, possible, unlikely, unassessable) and the Naranjo algorithm. Causality is assessed for individual ICSRs and also at the aggregate level during signal evaluation.

WHO-UMC Causality Assessment System; GVP Module VI

Council for International Organizations of Medical Sciences

An international non-governmental organisation that has produced influential guidelines and forms for pharmacovigilance, most notably the CIOMS I form — the original template for expedited adverse drug reaction reporting. CIOMS working groups have shaped global PV standards across signal detection, benefit-risk assessment, and pharmacoepidemiology. The CIOMS VI and CIOMS VIII reports are particularly influential for signal detection methodology.

CIOMS I–X Reports; ICH E2B(R3)

Clinical Trial Authorisation

The regulatory approval required from a national competent authority (NCA) or the EMA before a clinical trial can be initiated on human subjects within the European Economic Area. Under EU CTR 536/2014, CTAs are managed centrally through the Clinical Trial Information System (CTIS). Sponsors holding CTAs must meet ongoing safety reporting obligations including SUSAR expedited reports and annual DSURs.

EU CTR 536/2014; Directive 2001/20/EC (repealed)

Drug-Induced Liver Injury

Hepatotoxicity caused by a medicinal product, occurring as an adverse drug reaction affecting the liver. DILI is one of the most common reasons for post-marketing drug withdrawals and is a focus of safety monitoring in clinical trials and post-authorisation studies. Hy's Law — serum ALT >3× ULN combined with total bilirubin >2× ULN — is a key clinical indicator of serious DILI during development.

FDA Guidance on DILI (2009), GVP Module VI

Statistical Disproportionality Analysis for Signal Detection

A quantitative method for detecting potential adverse drug reaction signals in spontaneous reporting databases by comparing the observed frequency of drug-event combinations to the frequency expected if there were no association. Common methods include proportional reporting ratio (PRR), reporting odds ratio (ROR), and Bayesian approaches such as EBGM. These analyses are applied to FAERS, EudraVigilance, and VigiBase to identify new safety signals warranting further investigation.

GVP Module IX; EMA/706628/2013; Evans et al. (2001) Drug Saf

Development Safety Update Report

A periodic safety report submitted annually during the clinical development of an investigational product, covering all clinical trial data for the product globally. The DSUR replaced the national annual safety reports in ICH regions and is harmonised across FDA, EMA, and PMDA. It includes a line listing of SUSARs, cumulative safety summaries, and a benefit-risk evaluation in the context of the development programme.

ICH E2F, GVP Module VII (P-II)

Empirical Bayes Geometric Mean

A Bayesian disproportionality statistic used in pharmacovigilance signal detection that measures the ratio of observed to expected adverse event reports for a drug-event combination, shrunk toward the null using an empirical Bayes prior. EBGM is the central measure used by the FDA's Empirical Bayes Data Mining (MGPS) algorithm applied to FAERS. An EBGM05 (lower 95% confidence bound) ≥ 2 is commonly used as a signal threshold.

DuMouchel (1999) Drug Saf; FDA FAERS Signal Detection Guidance

European Union Drug Regulating Authorities Pharmacovigilance

The European database for the collection and management of individual case safety reports (ICSRs) for medicines authorised in the European Economic Area. Marketing authorisation holders and national competent authorities are required to submit ICSRs to EudraVigilance electronically using the ICH E2B(R3) standard. The EMA uses EudraVigilance data for signal detection and safety monitoring across all authorised medicinal products.

Regulation (EU) 1235/2010, GVP Module VI, EMA/813938/2011

Adverse Reaction Expectedness Assessment

The determination of whether an adverse reaction is listed in the reference safety information (RSI) for a medicinal product, which for clinical trials is the Investigator's Brochure and for marketed products is the approved Summary of Product Characteristics or equivalent. An "unexpected" adverse reaction is one that is not consistent in nature, severity, or frequency with the RSI. Unexpectedness, combined with seriousness and causality, determines whether a case qualifies as a SUSAR requiring expedited reporting.

ICH E2A, ICH E2D; GVP Module VI

Expedited Individual Case Safety Report

An ICSR that must be submitted to regulatory authorities within compressed timeframes — typically 7 calendar days for fatal or life-threatening unexpected SUSARs, and 15 calendar days for other serious unexpected SUSARs. Post-marketing expedited reports are required for serious unexpected spontaneous reports and certain solicited cases. Failure to submit expedited reports within the required timelines is a major GMP/GVP compliance risk.

ICH E2A, ICH E2D; 21 CFR 312.32; GVP Module VI

FDA Adverse Event Reporting System

The FDA's spontaneous reporting database that receives ICSRs for medicinal products and therapeutic biologics approved or marketed in the United States. Healthcare professionals, consumers, and manufacturers submit reports to FAERS (formerly AERS), which the FDA uses for post-marketing safety surveillance and signal detection. FAERS data are publicly available and widely used in pharmacoepidemiological research.

21 CFR Part 314.81, 21 CFR 310.305, FDA FAERS Public Dashboard

Good Pharmacovigilance Practices

The European Medicines Agency's framework of guidelines governing pharmacovigilance for medicinal products in the EU/EEA, organised into modules covering key activities such as ICSR reporting, signal management, PSUR/PBRER submissions, PSMF, risk management, and post-authorisation safety studies. GVP modules are legally binding for MAHs holding EU marketing authorisations and replace the earlier Volume 9A guidance. The modules are regularly updated by the EMA to reflect evolving regulatory expectations.

GVP Modules I–XVI, Directive 2010/84/EU, Regulation (EU) 1235/2010

ICH Guideline E2A — Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

The foundational ICH guideline establishing definitions for serious adverse events (SAEs) and unexpected adverse drug reactions during clinical development, and setting standards for expedited (15-day and 7-day) safety reporting. ICH E2A defines key terms including "serious", "unexpected", and "related", which underpin all pharmacovigilance reporting obligations globally. It remains the reference standard for clinical trial safety reporting in the US, EU, Japan, and other ICH regions.

ICH E2A (1994)

ICH Guideline E2B — Electronic Transmission of Individual Case Safety Reports

The ICH guideline defining the data elements and electronic format for transmitting individual case safety reports (ICSRs) between pharmaceutical companies and regulatory authorities. ICH E2B(R3), the current version, uses the HL7 FHIR-based format and is required for EudraVigilance, FDA FAERS, and PMDA VigiBase submissions. Compliance with E2B(R3) is mandatory for all MAHs and sponsors submitting ICSRs electronically.

ICH E2B(R3) (2016); EMA/813938/2011

ICH Guideline E2C — Periodic Benefit-Risk Evaluation Report (PBRER)

The ICH guideline governing the content and format of periodic safety reports for marketed medicinal products, culminating in the PBRER (also called PSUR in EU/EMA terminology). ICH E2C(R2) introduced the benefit-risk evaluation framework as the centrepiece of the periodic report, replacing the earlier summary tabulations focus of E2C(R1). The guideline is implemented in the EU through GVP Module VII and in the US through FDA guidance on PSURs for marketed products.

ICH E2C(R2) (2012); GVP Module VII

ICH Guideline E2D — Post-Approval Safety Data Management

The ICH guideline establishing definitions and standards for post-marketing safety reporting, including spontaneous reports, literature cases, and solicited reports from organised data collection systems. ICH E2D aligns with E2A definitions for seriousness and expectedness and defines the obligations for expedited post-marketing ICSR submissions. It forms the international basis for how MAHs manage and report spontaneous adverse drug reaction cases after approval.

ICH E2D (2003)

ICH Guideline E2E — Pharmacovigilance Planning

The ICH guideline that introduced the concept of the pharmacovigilance plan as a component of the risk management system, to be submitted at the time of marketing authorisation application. ICH E2E recommends a structured safety specification summarising important identified risks, important potential risks, and missing information, which forms the basis for the EU Risk Management Plan and the FDA REMS. It established the framework that evolved into the current RMP and PSMF requirements.

ICH E2E (2004); GVP Module V, FDA REMS Guidance

ICH Guideline E2F — Development Safety Update Report

The ICH guideline that defines the structure, content, and submission timing of the Development Safety Update Report (DSUR) for investigational products in clinical development. ICH E2F harmonised the previously divergent national annual safety report formats across FDA, EMA, and PMDA, creating a single globally accepted report. It requires an annual review of the clinical investigator's brochure, SUSAR line listings, and a cumulative benefit-risk evaluation.

ICH E2F (2010)

Individual Case Safety Report

The fundamental unit of pharmacovigilance data, documenting a single adverse drug reaction or adverse event in an individual patient. An ICSR must contain a minimum dataset: an identifiable patient, a suspect medicinal product, a suspected adverse reaction, and an identifiable reporter. ICSRs are submitted to regulatory databases such as EudraVigilance, FAERS, and VigiBase, and form the primary data source for spontaneous signal detection.

ICH E2B(R3), GVP Module VI

Investigational New Drug Application

The application submitted to the FDA before a new drug or biologic can be studied in human subjects in the United States, containing preclinical data, manufacturing information, and a clinical protocol. An active IND allows shipment of investigational product across state lines and authorises clinical investigation under FDA oversight. Sponsors holding INDs have ongoing safety reporting obligations, including 15-day expedited IND safety reports for unexpected serious suspected adverse reactions.

21 CFR Part 312, ICH E6(R2)

Listedness / Labelled Status of an Adverse Reaction

The determination of whether an adverse reaction is included in the current approved labelling for a medicinal product, equivalent to expectedness for post-marketing purposes. A reaction is "listed" if it appears in the Summary of Product Characteristics (SmPC) in the EU or the US Prescribing Information (USPI) in the US. An "unlisted" or unexpected serious adverse reaction from spontaneous reports triggers expedited 15-day reporting obligations for the MAH.

ICH E2D; GVP Module VI; 21 CFR 314.81

Marketing Authorisation Application

The regulatory submission made to the EMA (for centralised procedure) or national competent authorities to obtain approval to market a medicinal product in the EU/EEA. An MAA must include a Module 1.8 pharmacovigilance section containing the Risk Management Plan, PSMF summary, and PV system description. Approval of the MAA confers marketing authorisation holder status with ongoing GVP obligations.

Regulation (EC) 726/2004; Directive 2001/83/EC; GVP Module V

Marketing Authorisation Holder

The company or individual that holds the marketing authorisation for a medicinal product and bears primary legal responsibility for its pharmacovigilance system. The MAH must maintain a Pharmacovigilance System Master File (PSMF), appoint a Qualified Person for Pharmacovigilance (QPPV), and submit periodic safety reports, ICSRs, and Risk Management Plans to relevant authorities. In the US, the equivalent entity is the NDA/BLA holder.

Directive 2001/83/EC Art. 104; GVP Module I

FDA MedWatch Adverse Event Reporting Program

The FDA's safety information and adverse event reporting programme, through which healthcare professionals and consumers can voluntarily submit reports of suspected adverse drug reactions using the MedWatch 3500 form. Mandatory reports from manufacturers, importers, and packers use the MedWatch 3500A form and must comply with timelines in 21 CFR 314.81. MedWatch reports populate the FAERS database and are a primary source for post-marketing signal detection in the US.

21 CFR 314.81, 310.305; FDA MedWatch Programme

National Competent Authority

The governmental body responsible for regulating medicinal products within a specific country, including granting marketing authorisations (for nationally approved products), receiving and evaluating ICSRs, and overseeing GVP compliance for MAHs operating in their jurisdiction. Examples include the MHRA (UK), BfArM and PEI (Germany), ANSM (France), and Health Canada. NCAs collaborate through the PSUR/PBRER worksharing procedure and EudraVigilance for pan-EU safety monitoring.

Directive 2001/83/EC; Regulation (EU) 1235/2010

New Drug Application

The application submitted to the FDA requesting approval to market a new small-molecule drug in the United States, containing full reports of preclinical studies, clinical trial results, manufacturing information, and proposed labelling. Approval of an NDA confers the right and obligation to market the drug in the US, with ongoing pharmacovigilance responsibilities including expedited safety reporting, periodic safety reporting, and label change obligations. The equivalent submission in the EU is the MAA.

21 CFR Part 314; FD&C Act §505

Periodic Benefit-Risk Evaluation Report

The internationally harmonised periodic safety report for marketed medicinal products, defined by ICH E2C(R2), that evaluates cumulative safety data and places it in the context of a product's benefits. The PBRER is submitted on Data Lock Point (DLP)-based schedules defined in the European Union Reference Date (EURD) list for EU products, and is also accepted by FDA in lieu of a traditional US periodic report. It replaces the older PSUR format in ICH regions and is structured around a benefit-risk conclusion.

ICH E2C(R2); GVP Module VII; FDA Guidance (2016)

Periodic Safety Report (PSUR/PBRER/DSUR/ASR)

Any of the regular aggregate safety reports required by regulatory authorities to provide a cumulative and contextualised review of the safety profile of a medicinal product over a defined reporting period. For marketed products, this includes the PSUR/PBRER; for investigational products, the DSUR or ASR. Periodic reports allow regulatory agencies to assess whether the safety profile has changed materially since authorisation and whether the benefit-risk balance remains favourable.

ICH E2C(R2), ICH E2F; GVP Modules VII, VIII

Pharmacovigilance System of a Marketing Authorisation Holder

The organisational structure, responsibilities, processes, and resources used by an MAH to fulfil its pharmacovigilance obligations, including ICSR collection and reporting, signal detection, aggregate reporting, and risk management. The system must be described in the Pharmacovigilance System Master File (PSMF), be overseen by a QPPV, and be audited regularly. Inspections of the PV system by NCAs or the EMA can result in variation requests, warnings, or suspension of marketing authorisations.

Directive 2001/83/EC Art. 104; GVP Module I

Proportional Reporting Ratio

A frequentist disproportionality measure used in signal detection that compares the proportion of reports for a specific adverse event for the drug of interest versus the proportion of that adverse event among all other drugs in the database. A PRR ≥ 2 with a chi-squared statistic ≥ 4 and at least 3 cases is the threshold commonly used by the MHRA. The PRR is one of the two foundational disproportionality statistics alongside the ROR, and is simpler to compute but slightly less robust than Bayesian alternatives for rare events.

Evans et al. (2001) Drug Saf; MHRA Signal Detection SOP; GVP Module IX

Pharmacovigilance System Master File

A detailed description of the pharmacovigilance system maintained by the MAH, required to be kept current and accessible to the QPPV and competent authorities at all times. The PSMF must include the QPPV's CV and contact details, an organisational chart, a description of computerised systems, summaries of PV processes, quality system information, and an audit log. It is one of the most frequently inspected documents in EU GVP inspections and must reflect the actual operating state of the PV system.

GVP Module II; Directive 2010/84/EU Art. 104a

Periodic Safety Update Report

The EU/EMA terminology for the periodic aggregate safety report for marketed medicinal products, equivalent to the PBRER in ICH terminology. PSURs are submitted on schedules defined in the EURD list, covering cumulative safety data since the International Birth Date (IBD). Since the implementation of ICH E2C(R2), the PSUR format has been largely superseded by the PBRER structure, though the term PSUR remains in common use in EU regulatory contexts.

GVP Module VII; Regulation (EU) 1235/2010; ICH E2C(R2)

Qualified Person for Pharmacovigilance

The named individual responsible for the oversight and management of the pharmacovigilance system of an MAH holding EU/EEA marketing authorisations, and the single point of contact for regulatory authorities on safety matters. The QPPV must reside and operate in the EU/EEA, must have appropriate qualifications and experience, and bears legal accountability for the MAH's GVP compliance. Each MAH must have a designated QPPV listed in the PSMF and notified to the EMA in EudraVigilance.

GVP Module I; Directive 2001/83/EC Art. 104(3)

Risk Evaluation and Mitigation Strategy

An FDA-required risk management programme for drugs and biologics with serious safety concerns that cannot be adequately managed through labelling alone. REMS may include medication guides, communication plans, or elements to assure safe use (ETASU) such as restricted distribution networks, required patient monitoring, or provider certification programmes. The FDA can require a REMS at the time of approval or post-marketing if new safety information warrants additional risk minimisation.

FD&C Act §505-1; 21 CFR Part 208; FDA REMS Guidance (2019)

Risk Management Plan

A comprehensive document submitted to the EMA as part of an MAA (and updated throughout the product lifecycle) that describes the safety profile, pharmacovigilance activities, and risk minimisation measures for a medicinal product. An RMP contains a safety specification (important identified and potential risks, missing information), a pharmacovigilance plan, and a risk minimisation plan. The US equivalent is the REMS, though the two frameworks differ substantially in scope and structure.

GVP Module V; Regulation (EU) 1235/2010

Reporting Odds Ratio

A disproportionality statistic for signal detection in spontaneous reporting databases that functions as a case-control analogue — the ratio of the odds of reporting a specific adverse event for the drug of interest versus the odds for all other drugs. The lower bound of the 95% confidence interval of the ROR (ROR025) > 1 is a commonly used signal threshold in EudraVigilance signal detection. The ROR is slightly more conservative than the PRR for rare events and is widely used in pharmacoepidemiological literature.

van Puijenbroek et al. (2002) Pharmacoepidemiol Drug Saf; GVP Module IX

Pharmacovigilance Safety Database

The validated electronic system used by an MAH to collect, manage, code, and report adverse drug reaction data, including spontaneous reports, clinical trial safety data, literature cases, and solicited reports. Common commercial safety databases include Veeva Vault Safety (formerly Oracle Argus Safety), IQVIA ARISg, and Paladin. The safety database must be validated, maintained in a qualified state, and its processes described in the PSMF.

GVP Module I, Module II; EU GMP Annex 11; 21 CFR Part 11

ICH E2A Seriousness Criteria for Adverse Events

The set of conditions that define a serious adverse event (SAE): death, life-threatening condition, required or prolonged hospitalisation, persistent or significant disability/incapacity, congenital anomaly/birth defect, or other medically important condition. These criteria, established in ICH E2A and used globally, determine whether an adverse drug reaction requires expedited reporting. The distinction between serious and non-serious events is foundational to all pharmacovigilance reporting frameworks.

ICH E2A; 21 CFR 312.32; GVP Module VI

Pharmacovigilance Signal Detection

The systematic process of identifying new, clinically relevant safety information in spontaneous reports and other data sources that may represent a new risk or a change in a known risk for a medicinal product. Signal detection uses both quantitative methods (disproportionality analysis, e.g., PRR, ROR, EBGM) and qualitative clinical review. In the EU, EMA conducts centralised signal detection in EudraVigilance under GVP Module IX, and MAHs are required to conduct their own signal detection activities.

GVP Module IX; EMA/706628/2013

Suspected Unexpected Serious Adverse Reaction

An adverse reaction that is serious, unexpected (not listed in the reference safety information), and for which there is at least a reasonable possibility of a causal relationship with the investigational medicinal product under study. SUSARs are the primary safety reporting obligation for clinical trial sponsors and must be submitted to regulatory authorities within 7 days (fatal/life-threatening) or 15 days (all other serious) of the sponsor's awareness. SUSARs are line-listed in the DSUR and reported to EudraVigilance.

ICH E2A; GVP Module VI (P-II); 21 CFR 312.32

UK MHRA Yellow Card Adverse Drug Reaction Reporting Scheme

The MHRA's spontaneous adverse drug reaction reporting system in the United Kingdom, named after the yellow paper forms originally used by healthcare professionals to submit reports. Yellow Card reports are submitted by healthcare professionals, patients, and caregivers, and are the primary source of post-marketing safety data for MHRA signal detection. Since Brexit, UK MAHs must submit ICSRs to the Yellow Card scheme separately from EudraVigilance, using UK-specific ICH E2B formats.

Human Medicines Regulations 2012 (SI 2012/1916); MHRA Guidance on Adverse Drug Reaction Reporting