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Pharmacovigilance Tutorials | Interview Questions Tutorial

  • What is Pharmacovigilance?
  • Importance of Pharmacovigilance
  • History of Pharmacovigilance
  • Evolution of Pharmacovigilance in India
  • What is an Adverse Drug Reaction (ADR)?
  • What is an Adverse Event(AE)?
  • What is the difference between an Adverse Event(AE) & an Adverse Drug Reaction (ADR)?
  • What is the difference between an Adverse Event(AE) & a Side Effect?
  • What is a Serious Adverse Event (SAE)?
  • What is a Suspected Adverse Drug Reaction?
  • What is an Unexpected Adverse Reaction?

What is an Individual Case Safety Report (ICSR)?

  • Validity criterias of an ICSR
  • What is Labelling Assessment?
  • What is Causality Assessment?
  • What is Seriousness Assessment?
  • Pre-Marketing vs. Post-Marketing Pharmacovigilance
  • Risk Management Plans (RMPs)
  • What is a Signal?
  • Signal Detection
  • Risk-Benefit Ratio Analysis
  • Pharmacovigilance Audits and Inspections
  • Source of ADR Reports
  • What are Unsolicited Reports?
  • What are Solicited Reports?
  • Sources of Clinical Trial Solicited Reports
  • Sources of Post-Marketing Solicited Reports
  • What are Spontaneous Adverse Event Reports?
  • Spontaneous Reporting Systems and Databases
  • FDA Adverse Event Reporting System (FAERS)
  • EudraVigilance: Enhancing Pharmacovigilance in the European Union
  • Patient Support Programs (PSPs)
  • Patient Assistance Programs (PAPs)
  • Compassionate Use Studies (CUs)
  • What is a Safety Report?
  • ICSR: Individual Case Safety Report
  • SUSAR: Suspected Unexpected Serious Adverse Reaction
  • PSUR: Periodic Safety Update Report
  • DSUR: Development Safety Update Report
  • PADER: Post-Approval Drug Experience Report
  • PBRER: Periodic Benefit-Risk Evaluation Report
  • Regulatory Reporting Timelines
  • What is MedDRA?
  • Governance of MedDRA
  • Scope, Structure, and Characteristics of MedDRA
  • Maintenance of MedDRA
  • MedDRA Hierarchy
  • MedDRA Tools: Browsers and MVAT (MedDRA Version Analysis Tool)
  • MedDRA: Points to Consider (PTC)
  • Standardized MedDRA Queries (SMQs)
  • What is WHO-DD?
  • Governance of WHO-DD
  • Scope, Structure, and Characteristics of WHO-DD
  • Maintenance of WHO-DD
  • Methods of Causality Assessment
  • WHO-UMC Scale for Causality Assessment
  • Naranjo Algorithm for Causality Assessment
  • Bradford Hill Criteria for Causality Assessment
  • CIOMS/WHO Scale for Causality Assessment
  • Difference between CIOMS/WHO Scale and WHO-UMC Scale
  • French Imputability Assessment
  • What is Labeling?
  • What is a Drug Label?
  • Types of Labelling Documents
  • Various Labeling Documents are used in Different Countries
  • Labelling Documents used in India
  • Investigator's Brochure (IB)
  • Core Data Sheet (CDS)
  • Company Core Data Sheet (CCDS)
  • United States Prescribing Information (USPI)
  • Summary of Product Characteristics (SmPC)
  • Patient Information Leaflets (PIL)
  • Japanese Package Insert (JPI)
  • Over-The-Counter (OTC) Labels
  • Consumer Medicine Information (CMI)
  • Product Monograph
  • Package Inserts
  • Role of pharmacovigilance in different phases of clinical trials
  • Adverse Event Reporting and Management in Clinical Trials
  • Investigator's Responsibilities in Reporting Adverse Events
  • Sponsor's Responsibilities in Reporting Adverse Events
  • International Regulations in Pharmacovigilance
  • Good Pharmacovigilance Practices (GVP) Guidelines
  • What are Medication Errors?
  • What is Off-Label Use?
  • What is Lack of Efficacy?
  • What is Occupational Exposure?
  • What is Overdose?
  • What is Drug Misuse?
  • What is Drug Abuse?
  • What is Disease Progression?
  • What are Drug Interactions?
  • What are Drug-Food Interactions?
  • What is Idiosyncrasy?
  • What is Teratogenicity?
  • Data Mining and Signal Detection Methods in Pharmacovigilance
  • Communication of safety information to healthcare professionals and patients in Pharmacovigilance
  • Labeling Changes and Updates in Pharmacovigilance
  • Risk Evaluation and Mitigation Strategies (REMS)
  • Public Health Advisories and Alerts in Pharmacovigilance
  • Use of Artificial Intelligence and Machine Learning in Pharmacovigilance
  • Real-world Evidence and Big Data in Pharmacovigilance
  • Pharmacovigilance Interview Questions & Answers for Freshers

Module 1: Introduction to Pharmacovigilance

Module 2: pharmacovigilance & drug safety terminologies, module 3: pharmacovigilance lifecycle, module 4: sources of adr reports, module 5: drug safety reports, module 6: meddra coding, module 7: who-drug dictionary, module 8: causality assessment, module 9: labelling assessment, module 10: pharmacovigilance in clinical trials, module 11: pharmacovigilance regulations and guidelines, module 12: special situations in pharmacovigilance, module 13: safety surveillance and assessment, module 14: communication and risk minimization, module 15: emerging trends in pharmacovigilance, module 16: pharmacovigilance interview questions & answers, join our community on telegram, join the biggest community of pharma students and professionals..

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An ‘ Individual Case Safety Report (ICSR)’, also known as an Adverse Event Report or Case Report Form, is a fundamental document used in pharmacovigilance and clinical research to record and document adverse events or side effects that occur in patients or subjects who are exposed to a particular medication, medical device, or therapeutic intervention.

The purpose of an ICSR is to collect and report information about any unexpected or unfavorable medical occurrences that may have happened to an individual during a clinical trial, post-marketing surveillance, or while using a particular healthcare product in routine medical practice.

Key components typically found in an Individual Case Safety Report include:

1. Demographic Information: This includes details about the affected individual, such as age, sex, weight, medical history, and any other relevant patient characteristics.

2. Suspected Product or Intervention: Information about the medication, medical device, or treatment that the individual was exposed to and may have caused the adverse event.

3. Adverse Event Description: A detailed account of the adverse event or side effect experienced by the individual, including the nature, onset, duration, severity, and any relevant factors that may have contributed to it.

4. Outcome: The outcome of the adverse event, whether it resulted in full recovery, residual effects, or death.

5. Concomitant Medications: Details of any other medications the individual was taking at the time of the adverse event, as they could potentially interact with the suspected product.

6. Reporter Information: Information about the person or entity submitting the report, such as healthcare professionals, patients, caregivers, or pharmaceutical companies.

ICSRs play a crucial role in pharmacovigilance and post-market surveillance, as they enable regulatory authorities and healthcare organizations to monitor the safety and risk profiles of drugs and medical products. The timely and accurate reporting of adverse events helps identify potential safety concerns, leading to appropriate regulatory actions if necessary and overall contributes to patient safety and public health.

individual case safety report definition

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Public Safety & Vigilance

A common platform for safety alerts, news and other important updates for medicinal products and medical devices from health regulatory authorities across the globe..

  • Individual Case Safety Report (ICSR)
  • Aggregate Safety Report (ASR) Writing
  • Signal management
  • Voluntary ADR reporting
  • - Individual Case Safety Report (ICSR)
  • - Aggregate Safety Report (ASR) Writing
  • - Signal management

Basics of ICSR

The following topics are covered as fundamental concepts in ICSR.

Key Definitions

ICSR validity criteria

Sources of ICSR

Types of ICSR reports

Adverse Drug Event (AE): Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered as related to the medicinal or investigational product.

Adverse Drug Reaction (ADR): An unwanted or harmful reaction experienced following the administration of a drug or combination of drugs under normal conditions of use and is suspected to be related to the drug. An ADR will usually require the drug to be suspended or discontinued or the dose reduction.

Day “0”/Initial Receipt date/Regulatory clock start date : The date of initial awareness/receipt date of a valid ICSR by a company/company’s representative, (Irrespective of weekend/holiday) is considered as “Day 0”. It is the start date of regulatory timeline for a case.

Company received date/Safety Received date/Central received date: It is the date when the Pharmacovigilance (Drug safety) department has received the valid ICSR information.

Country of Incidence : The country where the AE/ADR experienced by a patient irrespective of the country of reporter.

Regulatory timeline : The stipulated time period based on the type of ICSR defined by respective regulatory authority for submission of a case from its Day 0 to regulatory body.

The following four elements are considered for assessing the validity of an ICSR

  • Identifiable patient,
  • Identifiable reporter
  • A suspect drug and
  • An adverse event or adverse drug reaction.

Identifiable reporter : Any identifiable information for reporter such as qualification (e.g. physician, pharmacist, other healthcare professional, lawyer, consumer or other non-healthcare professional), name, initials, or address (e.g. reporter’s organisation, department, street, city, state or province, postcode, country, email, phone number).

Identifiable patient: Any identifiable information for patient such as initials, date of birth, age, age group, gestation period, or gender, medical record number (from general practitioner, specialist, hospital, or investigation), or any specific patient identification number.

A suspect drug: The generic name or brand name of the at least a single suspect drug/medicinal product.

An adverse event or adverse drug reaction: The information pertaining to adverse event, adverse drug reaction with a suspicious causal association with medicinal product.

Incomplete/Invalid case: Any case with the lack of any of the above specified four elements does not qualify for as a valid ICSR.

An Invalid/Incomplete ICSR can become valid/complete, upon receipt of any of the missing information from reporter.

The activities of Pharmacovigilance commence from pre-marketing stage of developmental drugs to the post-marketing phase of approved and marketed drugs. The sources of obtaining the patient’s safety information of a medicinal product can be classified into two categories based on marketing status of medicinal product.

  • Pre-Marketing sources : The safety information from clinical trial studies sponsored, conducted and supported by pharmaceutical manufacturer or sponsor. It is a regulatory obligation for sponsors to monitor the safety profile of development molecule and report the significant safety concerns (adverse drug reactions which are unexpected as per the reference safety information) to respective health authorities and local regulatory bodies within stipulated timelines by respective authority.

There are few subcategories which can come under pre-marketing source:

  • International clinical studies: The clinical trail period covering from Phase I to Phase III, where the patients/healthy volunteers are under strict clinical observance for monitoring of adverse experiences of medicinal product under development.
  • Compassionate use programmes: A special approval for a single patient/group of patients use having a disease with no satisfactory authorised therapies and who cannot enter clinical trials for the use of unauthorized or unapproved medicinal product which is not yet released into market.

2. Post-Marketing sources : After availing the marketing authorization for a medicinal product, Marketing Authorization Holder (MAH) is obliged to monitor the safety behavior of medicinal product for a significant period of time in a wide range of population exposure which included populations not exposed to medicinal product under interventional monitoring or clinical study, to make sure the proposed benefit risk profile of the medicinal product to the regulatory authority is consistent with no significant variations. The following are potential sources of safety information for a medicinal product after marketing.

  • Literature: The case study reports which originate from a health care professional or research professional in hospitals, research centers, post marketing studies and significant review articles (systematic and meta-analysis) published in either well established global medical databases (Medline, Embase) or from local un-indexed literature journals.
  • Legal: The safety information reported by lawyer on behalf of individual patient or group of patients concerned with occurrence of adverse reactions associated with medicinal product use.
  • Post marketing studies, registries and programmes: As part of routine and additional pharmacovigilance activities and risk minimization measures, MAH are obliged to conduct the post marketing studies, registries and programmes to address specific safety concern identified from public exposure and to present the positive benefit risk ratio of their respective medicinal product to regulatory authority.
  • Spontaneous reports: It is a broad range of source which provides safety information either from health care professional (HCP) or directly from consumer. It could be in two ways as follows:
  • Voluntary/Passive reporting: The safety information could be reported directly to health authorities (HA) from HCP and consumer by HA specific adverse event form or through toll free number provide in HA website. The HA would share the same information to respective drug manufacturer for necessary action required or for processing in their safety database.
  • Mandatory/Active reporting : The safety information is reported to manufacturer’s drug safety center by HCP or consumer either by submitting the company specific adverse event/reaction form for spontaneous reporting or by online reporting platforms in MAH’s website or by reporting through toll free number dedicated for drug safety. MAH submits the same safety information to respective HA within the stipulated timelines.

Based on the sources and the type of data collection, ICSRs are classified into two categories.

  • Solicited ICSRs: The ICSRs which where originating from a organised data collection systems are classified as solicited type. The following types of ICSRs comes under solicited category.
  • Interventional Clinical Trail/Studies
  • Non-Interventional Clinical Trial/Study
  • Non-Interventional Programmes
  • Patient Registries
  • Patient support & Market research programmes
  • Investigator Initiated clinical Trails, Compassionate use programmes etc.,

2. Non-solicited ICSRs: The ICSRs, which are originating from an Un-organised data collection systems are classified as Non-solicited type. The following types of ICSRs comes under Non-solicited category.

  • Literature Abstracts/Articles
  • Legal Cases reported by Lawyer on behalf of consumer (client)
  • Health authority case reports
  • Spontaneous reports from health care professionals and directly from consumers
  • Social media reports-Any ICSR information posted on a social websites like Facebook, Twitter etc.,

individual case safety report definition

              Overview on Types of ICSRs based on their source

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Ctd conversion.

In June 2010, The Medicines Control Council (MCC) announced the intention to implement the South African Common Technical Document (ZA CTD) format which will replace the current MRF1 and any applications still in MBR1 format.

From June 2011, submissions in ZA CTD format are mandatory (excluding veterinary medicines).

Freyr is currently working with many Global Pharmaceutical and Consumer Health Care companies in supporting them in planning and executing the CTD conversion requirement for the existing and new product registrations in South Africa enabling them to meet the MCC mandate.  For some of these global companies CTD conversion is a time consuming and a huge responsibility that needs careful planning and execution given their growing product portfolio in the African market.

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Good Manufacturing Practice

Good Manufacturing Practice is that part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standards.

  • Regular periodic or rolling quality reviews of all registered medicinal products, including export only products are conducted.
  • The Manufacturer and Holder of Certificate of Registration, where different, should evaluate the results of the review and an assessment should be made of whether corrective and preventative action or any revalidation should be undertaken.

Medicines Control Council’s (MCC)  general policy is that the standard to be used to assess compliance with current Good Manufacturing Practice (cGMP), is the South African Guide to Good Manufacturing Practice (SA guide to GMP).

  • Under Section 22C of the Act, all South African manufacturers should be licensed
  • The Act requires that overseas manufacturers of medicine supplied to South Africa should comply with the same or equivalent manufacturing standards as expected of South African manufacturers
  • When acceptable evidence of GMP compliance is not available, overseas manufacturers are inspected by the GMP Inspectorate before registration of the medicine is approved

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Medicines registration.

Medicines to be used in South Africa for both public and private sectors shall be duly registered with the national regulatory authority, the Medicines Control Council’s (MCC) in accordance with the provisions and requirements of the Medicines and Related Substances Control Act No. 101 of 1965 and the Regulations and Guidelines published in terms thereof.

A written notification from the Minister to the effect that the medicine is considered essential to national health; an expert report (which is not more than 2 (two) years old; a package insert (where the product has been approved) and a summary basis for the registration (SBRA) should be submitted with application.

The Registrar shall notify the applicant within 30 days of the date of receipt of the application and the Council shall, within 9 months make a decision with regard to the application.

The abbreviated medicine review process is based mainly on the expert reports of the pharmaco toxicological and clinical data.

Applications for Abbreviated Medicine Review Process (AMRP) can only be accepted if the product has been approved by the said authorities within the last three years of the license in the licensing country.

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Submissions publishing.

In June 2010, The Medicines Control Council (MCC) announced the intention to implement the South African common technical document (ZA CTD) format which will replace the current MRF1 and any applications still in MBR1 format.  From June 2011, submissions in ZA CTD format are mandatory (excluding veterinary medicines).

With the need for converting old format submissions to CTD format comes the opportunity for Market Authorization Holders (MAH) to plan and be ready for electronic submissions.  Freyr can compile submissions in eCTD format and print in paper format as required by the current MCC requirement. This allows the MAHs to be prepared for future eCTD requirements from MCC and enables efficient electronic submission dossier management.

Registrations and Submissions Information Management

Module 1 (Administrative 1.10 Foreign Regulatory Status) requirement from Medicines Control Council’s (MCC) requires the applicant to provide a list of countries in which an application for the same product is being applied for in South Africa has been submitted, dates of submission (if available). This should detail approvals (with indications).  Applicants must declare whether a marketing application for the medicine has been rejected in the countries listed under 1.10.1 prior to submission of the application in South Africa. If the medicine has been rejected, repeatedly deferred or withdrawn, then the MCC must be informed and the reasons supplied.

If no application has been submitted for registration in the country of origin, include a statement to provide the reason for this decision. It should be noted that aforementioned information is required to be provided in dossier however, it does not mean that this will help to speed up the review process.

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Freyr Global Regulatory Solutions and Services

An Individual Case Study Report (ICSR) is a safety service document which includes information required for reporting the adverse events and problems related to products and complaints filed by consumers with respect to any product. It is an important facet of adverse event reporting which is a source of data in PV (pharmacovigilance). The ICSR is most commonly associated with PV. To build a compliant ICSR , there are four elements which must be mentioned:

  • A diagnosed patient
  • A suspect drug
  • An adverse event

Adverse event reporting is a Regulatory requirement in most of the countries for pharmaceutical companies. It also provides data to the companies and drug Regulatory authorities that play a key role in assessing the risk-benefit profile of a given drug. The source of adverse event reports may include reports from:

  • Healthcare professionals or patients
  • Patient support programs
  • Clinical or post-marketing studies
  • Literature sources
  • Media including websites
  • Or, reported to drug Regulatory authorities themselves

The implementation of ICSR varies from drug to drug. The applicant must reach out to the Regulatory agency before submitting the reports to clarify the content of ICSR. More details about the content and guidance document of ICSR is available on the websites of the agencies.

Freyr’s expertise in handling various ICSR s and AERs can help you stay compliant with the norms of the agencies. To know more about creation, publishing and submission of ICSR, contact our experts at [email protected]

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This website has been translated to Spanish from English, and is updated often. It is possible that some links will connect you to content only available in English or some of the words on the page will appear in English until translation has been completed (usually within 24 hours). We appreciate your patience with the translation process. In the case of any discrepancy in meaning, the English version is considered official. Thank you for visiting esp.fda.gov/tabaco.

Individual Case Safety Report Replication: An Analysis of Case Reporting Transmission Networks

John van stekelenborg.

1 Global Medical Safety, Janssen, the Pharmaceutical Companies of Johnson & Johnson, Horsham, PA USA

2 Global Safety, GSK, Brentford, UK

Roman Haack

3 Bayer AG, Pharmacovigilance Analytics, Berlin, Germany

Ulrich Vogel

4 Global Patient Safety and Pharmacovigilance, Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany

5 Safety Analyses Innovation and Submission Readiness Lead, Global Pharmacovigilance, Sanofi, Bridgewater, NJ USA

Markus Krupp

6 Global Patient Safety, Merck Healthcare KGaA, Darmstadt, Germany

Kate Gofman

7 CVRM Unit, Global Patient Safety Physician, CMO Patient Safety, AstraZeneca, Gaithersburg, MD USA

Brian Dreyfus

8 Epidemiology Lead for Integrated Oncology, Bristol-Myers Squibb Company, Princeton, NJ USA

Manfred Hauben

9 Pfizer Inc, New York, NY USA

10 Department of Medicine, NYU Langone Health, New York, NY USA

Andrew Bate

11 Department of Non‑Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK

12 Department of Medicine at NYU Grossman School of Medicine, New York, NY USA

Associated Data

Introduction.

The basis of pharmacovigilance is provided by the exchange of Individual Case Safety Reports (ICSRs) between the recipient of the original report and other interested parties, which include Marketing Authorization Holders (MAHs) and Health Authorities (HAs). Different regulators have different reporting requirements for report transmission. This results in replication of each ICSR that will exist in multiple locations. Adding in the fact that each case will go through multiple versions, different recipients may receive different case versions at different times, potentially influencing patient safety decisions and potentially amplifying or obscuring safety signals inappropriately.

The present study aimed to investigate the magnitude of replication, the variability among recipients, and the subsequent divergence across recipients of ICSRs.

Seven participating TransCelerate Member Companies (MCs) queried their respective safety databases covering a 3-year period and provided aggregate ICSR submission statistics for expedited safety reports to an independent project manager. As measured in the US Food and Drug Administration (FDA)’s Adverse Event Reporting System (FAERS), ICSR volume for these seven MCs makes up approximately 20% of the total case volume. Aggregate metrics were calculated from the company data, specifically: (i) number of ICSR transmissions, (ii) average number of recipients (ANR) per case version transmitted, (iii) a submission selectivity metric, which measures the percentage of recipients not having received all sequential case version numbers, and (iv) percent of common ISCRs residing in two or more MAH databases.

The analysis reflects 2,539,802 case versions, distributed through 7,602,678 submissions. The overall mean replication rate is 3.0 submissions per case version. The distribution of the ANR replication measure was observed to be very long-tailed, with a significant fraction of case versions (~ 12.4% of all transmissions) being sent to ten or more HA recipients. Replication is higher than average for serious, unlisted, and literature cases, ranging from 3.5 to 6.1 submissions per version. Within the subset of ICSR versions sent to three recipients, a significant degree of variability in the actual recipients (i.e., HAs) was observed, indicating that there is not one single combination of the same three HAs predominantly receiving an ICSR. Submission selectivity increases with the case version. For case version 6, the range of the submission selectivity for the MAHs ranges from ~ 10% to over 50%, with a median of 30.2%. Within the participating MAHs, the percentage of cases that reside within at least two safety databases is approximately 2% across five databases. Further analysis of the data from three MAHs showed percentages of 13.4%, 15.6%, and 27.9% of ICSRs originating from HAs and any other partners such as other MAHs and other institutions.

Replication of ICSRs and the variation of available safety information in recipient databases were quantified and shown to be substantial. Our work shows that multiple processors and medical reviewers will likely handle the same original ICSR as a result of replication. Aside from the obvious duplicate work, this phenomenon could conceivably lead to differing clinical assessments and decisions. If replication could be reduced or even eliminated, this would enable more focus on activities with a benefit for patient safety.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40264-022-01251-7.

Ensuring the safety of medicines and vaccines through systematic collection and review of adverse event (AE) reports is core to pharmacovigilance (PV) signal detection [ 1 ]. Overall, this is a shared responsibility between patients, healthcare professionals, academic researchers, regulatory bodies, and pharmaceutical companies. Pharmaceutical companies are legally responsible for collecting and evaluating AE reports and continuously monitoring the evolving evidence, taking appropriate action to maintain favorable benefit-risk profiles for the medical therapies they produce.

Pharmaceutical companies are required to share the reports that they receive with other parties in a timely manner, for example, with other companies when there are co-marketing agreements in place, and with Health Authorities (HAs) based on varying reporting criteria. Even without co-marketing agreements, some Marketing Authorization Holders (MAHs) forward a report for a non-company drug to the local HA and/or manufacturer (if known) according to local requirements. These individual case safety reports (ICSRs) are validated and processed, often in paper format, requiring a significant level of manual inputs and reconciliation between various entities in a timely fashion. Current safety data exchange and reporting mechanisms are complex due to variable regulatory requirements for report sharing [ 2 ]. The growth of safety data [ 3 ], paired with the lack of international harmonization around reporting requirements, can potentially lead to data quality problems and negatively impact public health.

While the long-standing quality of case duplication in a single database has been recognized as a significant problem in PV [ 4 , 5 ], very little is known about the phenomenon of " replication ." Replication of AE reports between databases occurs, as discussed above, when ICSRs are submitted to any recipient (e.g., HAs and companies) and then re-reported to multiple additional recipients. The net result is that each ICSR's case data reside in numerous databases, and each is repeatedly processed by numerous stakeholders. Replication may also lead to case duplication within databases where multiple pharmaceutical companies submit the same report to the same HA for regulatory compliance [ 5 ], which is a challenge in itself. Quantitatively and qualitatively speaking, differences can occur between safety databases and downstream analytical systems. Efficiency and completeness/correctness of information are probably affected by replication. However, no data quantifying replication has been published.

Study Objectives

The objective of this study is to estimate the extent and nature of primary replication of ICSRs, i.e., reporting of ICSRs by one or multiple Marketing Authorization/Clinical Trial Authorization (MAH/CTA) holders to multiple HAs. Additionally, replication across MAH databases is assessed. Within the framework of transmitting ICSRs, it is helpful to distinguish between “primary transmission” and “secondary transmission.” For this paper, primary transmission is defined as the ICSR transmissions by the MAH/CTA holder of a pharmaceutical product. Secondary transmission is defined as further transmissions of these ICSRs from the recipients of the primary transmissions. The key recipients of primary transmission are HAs and partner companies. Additionally, in interventional clinical trials (ICTs), ICSRs are also sent by the CTA holder to Investigators and Ethics Committees/Institutional Review Boards (ECs/IRBs). For this paper, while ICSRs from clinical trials are in scope, reporting destinations other than HAs (e.g., Investigators and ECs/IRBs) are not, as the focus is on transmissions that will generally be stored in a reference database resulting in replication (Fig. ​ (Fig.1 1 ).

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Schematic representation of ICSR transmission. AE adverse event, DB database, EC ethics committee, EMA European Medicines Agency, FAERs FDA Adverse Event Reporting System, FDA Food and Drug Administration, HA health authority, HCP healthcare professional, ICSR  individual case safety report, ICT interventional clinical trial, IRB  institutional review board, KFDA Korean Food and Drug Administration, MAH Marketing Authorization Holder, MHRA  Medicines and Healthcare Products Regulatory Agency, VAERS vaccine adverse event reporting system. The flowchart is for illustration purposes only and is not intended to be complete or representative of every ICSR. Legend: Yellow = Primary Transmissions; Yellow/Dashed = Primary Transmissions of ICT cases to EC/IRB/Investigators (out-of-scope); Orange = Secondary Transmissions; Green = Other Transmissions. Note that literature reports are usually identified by multiple pharmaceutical companies, which then forward the reports to multiple HAs; and literature reports may be independently identified by HAs themselves

Specifically, with regard to those MAHs that participated in the analysis, the replication assessment aims to:

  • Retrospectively quantify the level of primary replication of ICSRs resulting from MAHs transmitting a given ICSR to multiple HAs.
  • Retrospectively quantify the level of inter-company replication of ICSRs using the presence of common Worldwide Unique Identification Numbers (WUCIN) in multiple safety databases of the TransCelerate Member Companies participating in the project.
  • Quantify the extent to which recipients have "complete information" regarding an ICSR, defined as having received all initial and subsequent case versions submitted by MAHs, for example, due to new follow-up information obtained.

The net result is that any transmitted ICSR resides—with some lag time—in multiple databases, and each case is repeatedly processed and assessed by multiple stakeholders and replicated across the globe. This situation precludes a "ground truth" or "canonical version" of the original AE.

Participating TransCelerate Member Companies (hereafter referred to as MAHs) analyzed their internal safety data and provided summary tabulations for a 3-year period (generally, 1 January 2018–31 December 2020, although 1 June 2018–31 December 2020 in one case) to assess the number of HAs to whom an ISCR was submitted as an expedited report. Cases submitted in an aggregate report and not in an expedited manner were not in scope. The date range was selected to account for significant changes to ICSR reporting to HAs (e.g., centralized reporting to EudraVigilance in the European Union). Therefore, the sampled period remains generalizable to current PV practice.

Basic Definitions and Nomenclature

The following nomenclature is used for this paper:

  • Case or ICSR: an individual case safety report submitted in an expedited manner that can have one or more versions.
  • Case Version: a specific version of an ICSR (e.g., Version 1 is the first version of the report, Version 2 is an updated version of the same report that was submitted in an expedited manner, usually containing follow-up information).
  • Submission: a Case Version submitted via expedited means to a specific HA.
  • Recipient: an HA receiving a submission from a MAH/CTA holder.
  • Primary Transmission: ICSR transmission by the MAH/CTA holder of a pharmaceutical product to the designated HA.
  • Overall Replication Rate = number of submissions/numbers of case versions.
  • Percentage of Total Case Versions as a Function of Number of Recipients = fraction of all case versions that are sent to one, two, three, etc. recipients.

The following is an example of these logically connected definitions:

  • Upon receipt of an AE report, an ICSR with a unique identifier is created in an MAH's Safety Database (e.g., the internal case identifier is 100356).
  • The MAH receives an additional three follow-up reports, resulting in four case versions of the ICSR. These are identified as 100356 (1), 100356 (2), 100356 (3), and 100356 (4).
  • Due to different HA demands for follow-up information, the MAH submits version 1 to two HAs, version 2 to three HAs, version 3 to two HAs, and version 4 to one HA. Therefore, the total number of submissions is eight for this ICSR. Note that, while this is a hypothetical example, the number of recipients is driven by reporting rules for each recipient. Some recipients may require an updated version, while others do not. Likewise, new or updated information on relatedness, expectedness, or seriousness can trigger different distribution rules for different versions of the same case.

In the example above, four case versions are sent by the MAH. The distribution of recipient counts is:

  • ○ One HA recipient: 25% of the four case versions.
  • ○ Two HA recipients: 50% of the four case versions.
  • ○ Three HA recipients: 25% of the four case versions.

The terms “submission: and “transmission” are used interchangeably in this paper.

Stratifications

In addition to defining the "counting units" as above, data corresponding to several case stratifications were collected, to assess whether specific case characteristics selectively drive replication:

  • Case Type: Spontaneous or Non-Spontaneous.
  • Healthcare Professional (HCP) confirmed: Yes or No.
  • Seriousness: Serious or Non-serious.
  • Listedness (per Core Data Sheet [CDS]): Unlisted or Listed.
  • Literature: Yes or No.

Data Collection Methodology for Marketing Authorization Holders (MAHs)

A detailed data collection methodology was designed for this study to characterize and quantify the replication level in the Primary Transmission process. Under this approach, the participating MAHs generated four independent data outputs (Online Resource 1: ICSR Primary Transmission Data Collection Methodology (referred to as Online Resource 1 Tables 1, 2, 3, and 4)), which are part of the Electronic Supplemental Material (ESM). Each MAH was requested to provide the following:

  • ○ Number of case versions, stratified by the five stratification variables.
  • ○ Number of case versions by version number from version 1 through 5 and aggregated for versions higher than 5.
  • ○ The average number of HA recipients of submissions by case version, for versions 1 through 5
  • ○ The average number of HA recipients of submissions for versions 6 or higher
  • ○ The average number of HA recipients as above, stratified by the five case attributes.
  • ○ Full distribution: count of case versions submitted as a function of the number of HA recipients (note: five of seven MAHs provided this data)
  • ○ Submission Selectivity Measure by case version (see Sect. 3.4 below)
  • ○ Percentage of case versions residing in two or more participating MAH Safety Databases (see Sect. 3.5 below)

Regarding data output 2, the choice to collect only the arithmetic mean (average) and submission counts for each MAH was driven by the need to keep anonymity among the MAHs. This limitation prevents further investigation of potential "interactions" between the various case attributes such as "Serious AND HCP Confirmed."

Submission Selectivity Measure

As discussed, different HAs may receive different case versions of the same case, resulting in a situation where some HAs are "blind" to at least some of the information at some time for the ICSR of interest. In other words, some HAs may have incomplete information when measured against the totality of available case versions. This study did not qualify the exact case attributes that are deviating most, and thus no impact to signal detection can be derived. However, an indicative measure has been developed which delivers a quantification of the incompleteness of case versions distributed. For the mathematical details of this submission selectivity measure, consult the ESM.

MAH Overlap Measure

Participating MAHs provided lists of WUCINs, which were compiled and analyzed for the presence of the same WUCIN in multiple MAH databases. Since WUCINs are used to uniquely identify a case throughout its lifecycle (including multiple transmissions), a WUCIN occurring in multiple MAH databases quantifies replication across MAHs.

All seven MAHs provided the data described in the data collection methodology with the following exception:

  • Two MAHs did not provide the list of WUCINs for Online Resource 1 Table 4 (ESM). Therefore, the results based on this table represent five MAHs.

ICSR volume reported for seven MCs makes up approximately 20% of case volume in the FAERS database.

Data from the seven MAHs covered 2,539,802 case versions, distributed through 7,602,678 submissions. This represents an overall replication rate of 7,602,678 / 2,539, 802 = 3.0 transmissions per case version. For Data output 4, the five MAHs contributed 1,681,388 associated WUCINs in the raw format as otherwise available through publicly available information (e.g., FAERS).

For anonymization, the seven MAHs are arbitrarily designated as MAH01 through MAH07. These designations are used throughout the Results section.

Case Version Volume

A significant range in overall case version volume exists for the seven MAHs (approximately 100,000 to slightly over 1,000,000). The median number of case versions for the seven MAHs is 294,396, while the mean is 406,303 case versions. Figure ​ Figure2 2 provides the median percentages for case versions across the seven MAHs combined for each case attribute, as well as by case version. In addition to large differences in case volume, significant variability is present across case attributes, for example, the relative abundance of spontaneous and clinical trial cases. The ESM shows the differences in each case attribute for the seven MAHs.

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Median percentage of case versions by case attribute and case version

Replication

Average number of recipients.

The results from Online Resource 1 Table 2 (ESM; Average Number of Recipients (ANR)) are summarized in Fig. ​ Fig.3. 3 . Trends in the ANR are (near) monotonically increasing for four of the seven MAHs, (MAH01, MAH03, MAH04, and MAH07), indicating that additional follow-up reports beyond Version 1 are distributed to increasingly more HAs. Two MAHs (MAH02 and MAH05) have a maximum around Versions 2 or 3, with the ANRs tailing off for the higher versions. Finally, one of the MAHs (MAH06) shows a continuously decreasing trend as the version number increases. The magnitude of the replication level varies from approximately 1.5 recipients for MAH07, Version 1, to over five recipients for the highest case versions of MAH04.

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Average number of recipients (ANR) by case version for each MAH

The average level of replication (not weighted by case volume) across all MAHs is shown in Table ​ Table1. 1 . The level of replication varies significantly from this average, however, for certain case strata, as shown in Fig. ​ Fig.4. 4 . Replication is slightly higher for spontaneous, HCP confirmed, serious, unlisted, and literature-reported cases. These differences are likely driven by reporting requirements, which are different for these various case strata.

Median and mean average number of recipients by case version

ANR average number of recipients, MAH marketing authorization holder

The median and mean are not corrected for the differing case version volumes of the seven MAHs

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Average number of recipients (ANR) by case version case attribute

Distribution of Number of Recipients

As discussed before, the simple arithmetic mean (or median) in combination with the submission count only provides a partial picture of the level of replication. In particular, the distribution of the fraction of case versions sent to a specific number of recipients is generally very long-tailed. For the five MAHs that provided this data, Fig. ​ Fig.5 5 shows the percentage of total case versions as a function of the number of recipients. While most case versions are submitted to fewer than ten recipients, the percentage of case versions sent to ten or more recipients (HAs) across these five MAHs is 12.4%. The individual MAH values for percent of case versions to ten or more recipients range from 0 to 26%. From the MAH perspective, the case versions submitted to ≥ ten recipients are approximately 12% of case versions but approximately 40% of submissions.

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Percent of total case versions vs. number of recipients. Main area = distribution tail. Picture-in-picture shows the complete distribution

Analysis of Named Recipients

As the average number of recipients is three (for all cases) to four (for serious and/or unlisted cases), the question arises whether these three or four recipients are typically the same HAs receiving the case submissions. A post hoc analysis of recipient combinations was conducted in three MCs, measuring the relative percentages of occurrence of unique combinations of HA recipients. Table ​ Table2 2 shows these recipient combinations and their relative abundance for those ICSR submissions made to three recipients. Therefore, while an average of three MAHs receive a case version, there is considerable variability in the make-up of these recipients, which is reflective of a MAH’s portfolio and marketing authorizations.

Top ten recipient combinations of Individual Case Safety Report (ICSR) submissions made to three recipients

Another way of looking at this recipient-specific data is to measure what percentage of submissions is sent to the top three combinations. For submissions sent to three recipients, this percentage is 51.9%, 78.2%, and 27.9%, respectively, for MAH1, MAH2, and MAH3.

Submission Selectivity

The Submission Selectivity Measure is shown in Fig. ​ Fig.6 6 for versions 1 through 10, grouped by case version for all seven MAHs. On average, the magnitude of the Submission Selectivity increases for a given MAH, leveling off after version 5. Focusing on Version 6, the magnitude of Submission Selectivity ranges from approximately 10% to well over 50%. As shown in the smoothing line, the variation tends to cluster around 30% for the higher versions.

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Submission selectivity by case version across the seven MAHs combined

MAH Overlap

The overlap between company (MAH) safety databases is shown in Fig. ​ Fig.7 7 for the five MAHs that provided the data requested in Online Resource 1 Table 4 (ESM). The vast majority of cases exist only in one company database, with a small percentage (approximately 2%) of cases that are shared ("replicated") in two or more company databases.

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Histogram of the WUCIN count and number of MAH databases that contain them

As the level of inter-MAH replication seemed rather low at 2%, an additional post hoc text analysis was done on the WUCINs provided by three of the five MAHs, where the sender's identifier was extracted from the WUCIN and subsequently classified as "MAH” versus "Non-MAH.” MAH cases can generally be identified within the WUCIN through unique identifiers for the sender. This analysis showed that a significant percentage of WUCINs originate with partners and HAs: the percentages of Non-MAH WUCINs for the three participating MAHs are 13.4%, 15.6%, and 27.9%.

Summary of Results

On average, the replication level of a case version is approximately 3.0, while serious unlisted cases are replicated on average in approximately four HA databases. Within this average of three recipients, the make-up of actual HAs is variable within a MAH and also between MAHs. In other words, even for an “average case version” that is submitted to three HAs, the actual recipients are not predominantly the same HAs. It should be clear that the variability in the specific HAs receiving a given report is much higher than simply inferred from the mean number of three recipients. In general, replication is higher for Spontaneous cases, HCP confirmed cases, Serious cases, Unlisted cases, and Literature cases. Considering both the submission volume and the actual ANR value, the most significant drivers for replication are Serious and Unlisted cases. This is perhaps not surprising because most HAs require at least serious unlisted cases to be reported in an expedited manner.

The other main observation concerns a very long-tailed distribution of the number of recipients, providing evidence that 12.4% of cases exist in ten or more HA databases.

The variability of information received by MAHs—as measured by the Submission Selectivity measure—shows that the Selectivity for Version 1 of an ICSR is close to 0, which implies that this version exists in the same manner across HA databases, at least initially. However, as case versions increase, the Submission Selectivity level increases, meaning that different HAs have different information in their respective databases. While explanations of this phenomenon are somewhat speculative (e.g., for a given HA, the report may no longer meet all the submission reporting rules), the inescapable fact remains that there is very rapidly no longer a "canonical version" with complete information regarding a case that resides in every MAH’s database. In other words, content becomes more divergent in all HA databases as the number of case versions increases, although how divergent is unknown.

The WUCIN analysis shows that a relatively low level (approximately 2%) of replication of unique cases exists across the safety databases of the participating MAHs. This, however, is representative of only the five MAHs that provided their data and therefore dependent on the co-marketing agreements between these MCs. Since large pharma companies often enter into dozens or even hundreds of these agreements, the additional text analysis on the WUCINs is deemed more representative of the extent of co-occurring cases in MAH databases. The overlap percentages in the databases of the three participating MCs (13.4%, 15.6%, and 27.9%) demonstrate that a significant fraction of cases originated from a partner’s or HA’s database.

Causes, Implications, and Mitigations of Individual Case Safety Report (ICSR) Replication

Across the participating MAHs, the level of replication in primary transmission for the most important cases (serious/unlisted) in PV results in a situation where each case version, on average, resides in four HA databases. The actual submission distribution is long-tailed, and over 10% of case versions are sent to ten or more recipients. As shown through the analysis of variation, these HA databases will not always have the same information, especially for higher versions where some versions may exist in one HA database but not another one. This is likely driven by specific reporting rules that may result in one recipient receiving a new version and another not receiving it. Other discrepancies may result in selective downgrades or nullifications of a case in certain countries, for example, if a product marketing authorization is changed, that then makes reporting inapplicable in a certain country. This situation results from the primary transmission process alone and is presumably exacerbated in scenarios where case versions are forwarded by their primary recipients to secondary ones. It should be noted that all analysis results are aimed at the “primary transmission” step, the first transmission of an ICSRs from the original report recipient (assumed to be a MAH) to the second recipient (assumed to be a HA). Additional transmissions may, of course, occur from the second recipient to further organizations, a step termed “secondary transmission.” This secondary transmission step inevitably increases the phenomenon of replication and fracturing of information. The magnitude of this secondary transmissions step was not directly measured in our analysis; however, the post hoc text analysis of WUCINs undertaken by three of the five MAHs provides some insights retrospectively into the path taken by an ICSR through which a WUCIN number has been added by each recipient. This magnitude could be more directly estimated by analyzing secondary reporting rules (e.g., from a receiving HA to a partner HA) or by direct measurement similar to our analysis.

While this secondary transmission process was not in scope for this paper, it is fair to say that an imperfect status quo in the PV world has been in effect for a while, with rework driven by the level of replication and a lack of canonical information apparently unavoidable and significant. Although consolidation of ICSR reporting (e.g., reporting for all products authorized within the European Economic Area; EEA) has attempted to simplify and reduce the replication issue regionally, it is apparent that further improvements in ICSR reporting processes may be in order as PV frameworks globally continue to mature and drive the creation of new databases to monitor the safety of products.

Several possible options to avoid replication and variation of information may be contemplated and investigated, including:

  • For literature cases, which represent a relatively small ICSR volume, and which are less time-critical, but where the highest levels of replication were observed in this study, a possible solution is managing the exchange of references through a single gateway.
  • The creation of a global solution, though not necessarily in the sense of a single centralized database, a distributed system would be conceivable as well, along the lines of the Sentinel Distributed Database [ 6 ]. Such an ICSR system, intended for use by both MAHs and regulators and in which each report is held once with the necessary safeguards for ICSR read/write privileges, would require buy-in from all stakeholders, including lawmakers, medical professionals, HAs, and MAHs. With harmonized approaches, a willingness to give up some level of control is exchanged for efficiency and completeness. The consensus around “big data” analytics is that data storage is affordable, and the value of analytics on data more than covers the cost of replicating and centralizing it for easy analytics. Looking farther ahead, the general concept of transmitting cases back and forth might also be outdated [ 7 ]; an alternative approach could be one fee-based institution where MAHs book-in, take up, and maintain cases similar to a collaboration platform; economies of scale allow for growing artificial intelligence (AI) support and advanced technology instead of micro-steps performed internally by MAHs, meaningful qualitative signal detection is possible in one large place where providers, MAHs, and HAs can adhere to the FAIR principles of data management (Findability, Accessibility, Interoperability, and Reusability) [ 8 ]. However, it is acknowledged that any type of (de) centralized canonical database is aspirational and requires a long process of consensus building. As current PV operational choices on reporting are based on local requirements, these reporting requirements would need to manifest themselves in corresponding extraction rules for retrieving the data from the global platform.
  • Alternatively, a significant degree of unification of worldwide regulatory requirements would go a very long way in assuring at least the similarity of content in each MAH's database. The requirement to send every case version to every HA, for example, coupled with intelligent systems to handle that reporting volume with automation, could be considered in the absence of one unique database. Obviously, this only addresses the question of diverging content and not the issue of multiple recipients. The creation of case-type specific solutions could be considered, specifically for literature cases. While literature cases do not represent a large case volume, this type of case does result in a high degree of replication. A specific approach that could prevent the inclusion or transmission of already existing literature references is the application of similarity measures for text comparison. In a similar field, Levenshtein distance [ 9 ] was applied for measuring redundancy in Electronic Health Records [ 10 ].
  • Other more advanced technologies that allow the identification and tracking of a "canonical" ICSR through some type of immutable tagging without the need for a central repository could be considered as well.

Admittedly, significant consensus among the pharmaceutical manufacturers and regulators on this subject would be a necessary condition even to start investigating the possibilities in this area. However, it is in the direct interest of patient safety that complete and timely information is always available to all stakeholders, and a global distributed shared database, centralized database, harmonization of reporting rules, or a trackable ICSR may function as a significant step towards that goal. Whether the phenomenon of “replication” by itself is sufficient to trigger any concrete action towards any of the solutions proposed above remains to be seen.

Study Limitations

Finally, there are limitations of this study:

  • The extent of replication described in this study is likely to be an underestimate of the true extent of replication as replication was conceptualized at a country/regional level. However, in some countries, different PV databases exist differentiated by, for example, marketed versus non-marketed products, prescription versus non-prescription, biologic versus non-biologic, etc., resulting in the ICSR being sent to multiple databases within a country.
  • This study covers primary transmission only; a network transmission model which accounts for how the recipient HA processes and shares data would allow for an estimate to quantify dataflows and assess submission selectivity across the network model. It is likely that this data is generalizable across the pharma industry. Independent of the size of a pharmaceutical company, MAHs are sending replicate reports to more or less the same or at least the same average number of HAs.
  • The variables in this study are not independent (e.g., there is likely some level of correlation between seriousness and listedness), and it would have been interesting to see which combination of factors leads to more replication. However, the design of this study required data to be submitted in aggregate by each MAH; therefore, these interactions could not be studied.

Conclusions

The main objective of the paper was to quantify the complexity of ICSR migratory patterns, as they result in the replication and divergence of information in stakeholders' information systems. This complexity is largely driven by the multitude of diverging reporting requirements across the globe and the numerous marketing agreements between MAHs.

Replication of ICSRs and the existence of fractured and incomplete safety information distributed across databases is demonstrated to be a real phenomenon. The average number of recipients per case version across the surveyed companies is approximately three recipients (four recipients for serious, unlisted cases), and there is additional variability in which actual HAs receive a case version. It was shown that a significant portion (12.4%) of case versions is submitted to ten or more HAs, making up about 40% of submissions.

A discussion on the concept of a globally distributed sharing platform in combination of retrieval rules corresponding to local regulatory requirements is perhaps best initiated and facilitated by an organization such as the ICH or a consortium of HAs.

Additional suggested research may include the exploration of secondary transmission from the initial recipients to additional parties. The value of which should be investigated.

In terms of potential solutions to alleviate the inefficiencies and inconsistencies resulting from the replication phenomenon, in-depth technical work is needed, for example, in the realm of ICSR tracing capabilities, (de)-centralized common database solutions, and other potential approaches.

Below is the link to the electronic supplementary material.

Acknowledgements

The authors worked as part of a project team organized by TransCelerate Biopharma Inc., which is funded by 20 organizations dedicated to making research and development, including pharmacovigilance monitoring and reporting, more efficient and effective in the pharmaceutical industry. The authors also gratefully acknowledge the support of their member company teams for the considerable effort involved in collecting data for this project. This includes the advice, insight, and revised data they offered during frequent quality checks. Thanks as well to Neal Grabowski (Sanofi) for workstream leadership support and Clint Craun (TransCelerate) for project management support.

Declarations

This work was supported by TransCelerate BioPharma Inc.

All authors, including John van Stekelenborg, Vijay Kara, Roman Haack, Ulrich Vogel, Anju Garg, Markus Krupp, Kate Gofman, Brian Dreyfus, Manfred Hauben, and Andrew Bate, declare no conflicts of interest. However, all authors affiliated with pharmaceutical companies are employees and, in some cases, stockholders of the companies. The views expressed in this article represent the authors' thoughts and are independent of their employers.

This declaration is not applicable as no human participants were involved and no protected/personal health information (PHI) was used. The data used for this study were metadata related to case transmissions, not safety case data itself.

Not applicable.

TransCelerate ensured collection, anonymization, and aggregation of member company safety data transmissions were performed and coordinated by a third-party project manager. The resulting datasets will remain confidential. Please see Electronic Supplementary Material for more information regarding data collection.

All authors contributed to the article's conception and design. All authors read and approved the final manuscript. Collection, anonymization, and aggregation of safety data were performed and coordinated by a third party project manager.

The original online version of this article was revised due to a retrospective Open Access order.

Change history

A Correction to this paper has been published: 10.1007/s40264-023-01272-w

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  • Specifications for Preparing and Submitting Electronic ICSRs and ICSR Attachments

GUIDANCE DOCUMENT

Specifications for Preparing and Submitting Electronic ICSRs and ICSR Attachments February 2020

This document provides current specifications for submitting individual case safety reports (ICSRs) and ICSR attachments in electronic form. The specifications apply to electronic submission of ICSRs for drug and biological products, studied under an investigational new drug application (IND); ICSRs from bioavailability/bioequivalence (BA/BE) studies conducted without an IND, and ICSRs for marketed drug and biological products and combination products to the FDA Adverse Event Reporting System (FAERS). The specifications do not apply to the following marketed biological products: prophylactic vaccines, whole blood or components of whole blood, human cells, tissues, and cellular and tissue-based products (HCT/Ps) regulated by FDA.

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ICH E2B (R3) Electronic transmission of individual case safety reports (ICSRs) - data elements and message specification - implementation guide - Scientific guideline

This document provides guidance on the implementation of the standard adopted by the ICH for electronic transmission of individual case safety reports (ICSRs). Read together with:  ICH guideline E2B (R3) - Step 5 - questions and answers

Keywords : Transmission identification, batch wrapper, message wrapper, case safety report, primary source, sender, literature reference, study identification, patient characteristics, parent-child/foetus report, reaction, event, results of tests, drug information, acknowledgement message

Current effective version

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guideline E2B (R3): Electronic transmission of individual case safety reports (ICSRs) - data elements ...

External links

  • ICH E2B (R3) presentation (see  ICH E2B (R3) presentation under E2A - E2F Pharmacovigilance: E2B(R3): WG Presentations / Trainings)

Related content

  • ICH: efficacy
  • Scientific guidelines

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Individual Case Safety Report (ICSR)

An Individual Case Study Report is an adverse event report for an individual patient.

Individual Case Safety Report (Synonym with Adverse Drug Reaction Report)

Individual Case Safety Report is a document in a specific format for the reporting of one or several suspected adverse reactions to a medicinal product that occur in a single patient at a specific point of time.

Individual Case Safety Report in the European Union

All of the available supporting documentation for the event must be described in this report.

For reporting purposes, done electronically in EU/EEA, the ICSR should contain the following 4 basic elements: An identifiable patient/subject; An identifiable reporter, A suspect drug or biological product, An adverse event or fatal outcome.

If any of these basic elements remain unknown after being actively sought by the applicant, manufacturer, or licensed manufacturer, the ICSR should not be submitted to the Competent Regulatory Authorities, but used in other pharmacovigilance activities such as, but not limited to, signal detection and PSUR reporting.

Other glossary definitions

Unanticipated serious adverse device effect (usade).

A Serious Adverse Device Effect which by its nature, incidence, severity, or outcome has not…

Off-label use

Situations where a medicinal product is intentionally used for a medical purpose not in accordance…

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Individual case safety reports--how to determine the onset date of an adverse reaction: a survey

Affiliation.

Background: The building blocks of a pharmacovigilance system depend primarily on good quality individual case safety reports (ICSRs), which are stand-alone summaries describing one or more suspected adverse reactions that occur while a subject is taking either an investigational or marketed medicinal product and may require expedited reporting to regulatory authorities. For regulatory reporting purposes, the information of an ICSR is usually captured on forms such as MedWatch 3500/3500A, CIOMS I, Vaccine Adverse Event Report System (VAERS) or Adverse Events Following Immunization (AEFI). ICSRs that are sent electronically must meet the standards for electronic transmission specified in the International Conference on Harmonisation (ICH) E2B (R2) guideline. In filling out these regulatory forms, there are some areas of ambiguity. One of these is what the 'date of event' (MedWatch) or 'reaction onset date' (CIOMS) is interpreted to be.

Objective: The aim of the survey was to determine the uniformity of responses for the onset date of an adverse reaction.

Methods: A pilot and three surveys of pharmacovigilance professionals were undertaken between February and July 2009 to determine the range of responses for the onset of an adverse reaction. A narrative of a subject admitted to hospital with a diagnosis of pneumonia was presented and the respondent was asked to pick the date of onset of the adverse reaction.

Results: The total number of respondents was 129. The results of the surveys indicated there was considerable variation in responses. These differences were based on different perspectives regarding the suspected adverse reaction. Some viewed the 'reaction' to be the first onset of signs and symptoms (even if non-specific), others considered the onset of the reaction to be the date of the diagnosis, while others considered the date to be when the reaction became serious.

Conclusion: By means of a survey, we have illustrated an example of the variability of determining the onset date of a suspected adverse reaction, and recommend that a criterion for onset time, i.e. beginning of signs or symptoms of the event, or date of diagnosis, be chosen as the standard. Once decided, this information should be incorporated into the company's case assessment documentation and staff appropriately trained, thus ensuring consistency across cases and minimizing the time spent in determining what date to use.

  • Adverse Drug Reaction Reporting Systems* / organization & administration
  • Adverse Drug Reaction Reporting Systems* / standards
  • Databases, Factual
  • Drug-Related Side Effects and Adverse Reactions / diagnosis*
  • Medical Records Systems, Computerized* / organization & administration
  • Medical Records Systems, Computerized* / standards
  • Pilot Projects
  • Surveys and Questionnaires

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  4. Safety as a value for businesses, Part 2

  5. 1. Session 1: Documentation, Resources & Implementation milestones

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COMMENTS

  1. PDF EU Individual Case Safety Report (ICSR) Implementation Guide

    July 2013. ICH agreed to use the International Organization for Standardization (ISO) Individual Case Safety Report (ICSR) standard ISO EN 27953-2 to meet the reporting requirements for E2B(R3): • EN ISO 27953-2:2011 Health Informatics, Individual case safety reports (ICSRs) in

  2. Individual Case Safety Reports

    The HL7 Individual Case Safety Report (ICSR) captures information needed to support reporting of adverse events, product problems and consumer complaints associated with the use of FDA regulated ...

  3. Individual case safety report

    Individual case safety report; Individual case safety report. A document providing information related to an individual case of a suspected side effect due to a medicine. Product emergency hotline. OUTSIDE WORKING HOURS. About us. What we do. Careers. Committees. Regulatory network. Languages.

  4. What is an Individual Case Safety Report (ICSR)?

    An 'Individual Case Safety Report (ICSR)', also known as an Adverse Event Report or Case Report Form, is a fundamental document used in pharmacovigilance and clinical research to record and document adverse events or side effects that occur in patients or subjects who are exposed to a particular medication, medical device, or therapeutic intervention.

  5. Basic fundamentals of Individual Case Safety Reports

    It is the start date of regulatory timeline for a case. Company received date/Safety Received date/Central received date: It is the date when the Pharmacovigilance (Drug safety) department has received the valid ICSR information. Country of Incidence: The country where the AE/ADR experienced by a patient irrespective of the country of reporter.

  6. What is AnIndividual Case Study Report (ICSR)?

    An Individual Case Study Report (ICSR) is a safety service document which includes information required for reporting the adverse events and problems related to products and complaints filed by consumers with respect to any product. It is an important facet of adverse event reporting which is a source of data in PV (pharmacovigilance).

  7. PDF Post-approval Safety Data Management Efinitions and Standards for ...

    Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting 3 3. SOURCES Of INDIVIDUAL CASE SAFETY REPORTS 3.1 Unsolicited Sources 3.1.1 Spontaneous Reports A spontaneous report is an unsolicited communication by a healthcare professional or consumer to a company, regulatory authority or other organization (e.g. WHO,

  8. Individual Case Safety Reports

    Abstract. Individual Case Safety Reports (ICSR) play a key role in assessing the risk-benefit profile of a given medicinal product. An ICSR is considered to be valid for reporting to a regulatory authority if it has at least one single identifiable patient, one identifiable reporter, one or more suspect adverse drug reaction, and one or more ...

  9. PDF Note for Guidance

    Safety Messages and Individual Case Safety Reports (ICSRs)' (Doc. Ref. EMA/H/20665/04/Final, Revision 1). The following aspects are outlined in detail: The mandatory electronic reporting essentials The data quality principles of ICSRs transmitted electronically The generation of a valid ICH Safety Message

  10. PDF EU Individual Case Safety Report (ICSR) implementation guide

    EN ISO 27953-2:2011 Health Informatics, Individual case safety reports (ICSRs) in pharmacovigilance — Part 2: Human pharmaceutical reporting requirements for ICSR (ISO 27953- 2:2011). Chapter IV of the Commission Implementing Regula tion (EU) No 520/2012 refers to the possibility of

  11. PDF Guidance for Industry

    individual case safety reports by identifying, and where necessary or advisable, by defining the data ... Successful electronic transmission of information relies on the definition of common data ...

  12. CFR

    Individual case safety report (ICSR). A description of an adverse drug experience related to an individual patient or subject. ICSR attachments. Documents related to the adverse drug experience described in an ICSR, such as medical records, hospital discharge summaries, or other documentation. Disability.

  13. Individual Case Safety Report Replication: An Analysis of Case

    Case or ICSR: an individual case safety report submitted in an expedited manner that can have one or more versions. Case Version: a specific version of an ICSR (e.g., Version 1 is the first version of the report, Version 2 is an updated version of the same report that was submitted in an expedited manner, usually containing follow-up information).

  14. PDF Ich Harmonised Guideline Safety Data: and Standards for And Reporting

    107 An expedited report is an individual case safety report that meets the requirements for reporting as 108 soon as possible, but no later than 15 calendar days after day zero (see Section 5.2, Reporting 109 Timeframes). 110 2.4 Primary Source 111 A primary source(s) is a person who provides facts about a case. Primary sources, often referred

  15. Specifications for Preparing and Submitting Electronic ICSRs and ICSR

    This document provides current specifications for submitting individual case safety reports (ICSRs) and ICSR attachments in electronic form. The specifications apply to electronic submission of ...

  16. PDF Guidelines for Detecting & Reporting Adverse Drug Reactions

    card concerns an Individual Case experienced ADRs, thus it is also called Individual Case Safety Report (ICSR). Individual Case Safety Report (ICSR) A document providing the most complete information related to an individual case at a certain point of time. An individual case is the information provided by a primary reporter to describe

  17. PDF Data Elements for T Individual Case Safety Reports E2b(R3)

    The format for individual case safety reports includes provisions for transmitting all the relevant data elements useful to assess an individual adverse drug reaction or adverse event report. The data elements are sufficiently comprehensive to cover complex reports from most sources, different data sets, and transmission situations or

  18. ICH E2B (R3) Electronic transmission of individual case safety reports

    This document provides guidance on the implementation of the standard adopted by the ICH for electronic transmission of individual case safety reports (ICSRs). Read together with: ICH guideline E2B (R3) - Step 5 - questions and answers

  19. (PDF) Individual Case Safety Reports

    Setting Reports were retrieved from VigiBase, the WHO global database of individual case safety reports, in January 2015. Patients Data for patients aged ≤17 years old were extracted.

  20. Individual Case Safety Report (ICSR)

    Individual Case Safety Report in the European Union All of the available supporting documentation for the event must be described in this report. For reporting purposes, done electronically in EU/EEA, the ICSR should contain the following 4 basic elements: An identifiable patient/subject; An identifiable reporter, A suspect drug or biological ...

  21. Individual case safety reports--how to determine the onset date of an

    Background: The building blocks of a pharmacovigilance system depend primarily on good quality individual case safety reports (ICSRs), which are stand-alone summaries describing one or more suspected adverse reactions that occur while a subject is taking either an investigational or marketed medicinal product and may require expedited reporting to regulatory authorities.

  22. Individual Case Safety Report Definition

    An Individual Case Safety Report (ICSR) is a description of an adverse drug experience15 related to an individual patient or subject.16 An ICSR is made up of data elements, such as the date of an adverse drug experience, the name of a suspect medical product, and the name of the initial reporter. Adverse reactions that occur when using Federal ...

  23. Individual Case Safety Report (ICSR) Definition

    An Individual Case Safety Report (ICSR) is an adverse event report for an individual patient and is a source of data in pharmacovigilance. As discussed in (Islam and Governa-tori 2018), the regulations: (a) specify the records and reports concerning adverse drug experi- ences on marketed prescription drugs for human use without approved new ...