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【召集人專欄】<藥物安全系列五> 藥廠的藥物安全事件處理流程(下) (Liang-Ni Wu)

Disclaimer: This article was prepared by Liang-Ni Wu in her personal capacity. The views and opinions expressed in this article are the author’s own and do not necessarily reflect the policy or view of Merck KGaA.

Article April 2017

Introduction of Case Flow for Pharmacovigilance in Pharmaceutical Industry – Part 2

Case Processing

After triage, the case may enter the processing step. The purpose of case processing is to ensure a standard and structured way to capture the case information in the safety database. This step may include data entry, coding (for the events and drugs), case evaluation and narratives writing. The personnel performing case processing are trained and provided with standard convention of data entry, coding, narratives writing and evaluation criteria. During case processing, there may be queries generated and raised to the reporter of the case. Queries addressed to the reporter may result in additional information reported, which may become a follow-up report and will be triaged and processed into the safety database. Case evaluation typically includes the assessment of causality (whether the event is related to the suspected drug), seriousness criteria (whether the event is serious, and if yes, whether it is fatal, life-threatening, requiring/prolonging hospitalization, resulting in temporary or permanent disability, resulting in congenital/birth defect, or medically important) and expectedness (whether it is listed/labelled in the product reference safety information /label). Some people asked what is the purpose of narratives writing, as it is a time-consuming task and not all personnel in the case flow are interested in reading narratives. Narratives written in the case processing step help the case evaluator to obtain a better picture about how the case occurred, diagnosed and developed, and factors influencing the diagnosis, seriousness and causality assessment. In clinical trials, the narratives prepared at the case-processing step can further be utilized and developed into case narratives in the final study report. 

Before the end of case processing step, quality control (QC) and approval must be done to ensure quality of the data and to control versions.

After a case is approved, a case version is generated. New information (follow-up report) received after the approval step should be assessed. The company should then decide if a new work flow should be started to create the next version for the case.

Regulatory Report Generation

After a case is approved and a version created, regulatory report can be generated from the safety database. If the case meets the expedited reporting criteria to a health authority, the company should submit the report accordingly. Expedited reporting means the case should be reported to a health authority within a few days (depending on the reporting timeline defined by different health authorities in different countries/regions, it can range from 24 hours to 15 working days, but the international standard for an expedited reporting refers to a timeline of 7-days or 15-days). The criteria for expedited reporting also vary across countries/regions, but usually it concerns the source of case (from clinical trials or post-marketing spontaneous, or solicited…etc.), seriousness of the case, causality assessment, expectedness and country of occurrence.

If a case does not meet the expedited reporting criteria to a health authority, it is not subjective to expedited reporting, and may be included in an aggregate or periodic safety report. The requirement of an aggregate or periodic safety report, the periodicity and its format also vary in different countries/regions and depends on the status of drug development (whether the drug is under clinical development and if the drug is already registered marketed, the status and type of registration/marketing, e.g., if it is newly marketed under new drug surveillance period, if it is a generic drug…etc.)    


Once a regulatory report is generated, it can be distributed internally (to colleagues in specific countries who require the report to submit to health authorities locally) or externally (based on contracts/agreements signed with other companies), and/or transmitted to health authorities directly as electronic reporting (e.g. to EudraVigilance via Gateway or Web solution).

The action of distribution/reporting looks simple and straightforward, but there are a lot of considerations and knowledge in the background. The personnel responsible for distribution/reporting should be aware of to whom where, by when and how, what to send. This know-how should be supported by the company’s regulatory intelligence.

The distribution/reporting step is also critical to determine if the company submits a safety report to a health authority correctly in time and if the company distribute the report to the other companies according to contracts/agreements, the distribution/reporting step is usually closely monitored and measured for compliance. 

If a company has only occasional cases, it is possible that every person in the team participates in the full case flow, meaning the person who collects a case also process it and report/distribute it. When the amount of cases is huge (say, in average a hundred reports per day), instead of hiring and training 40 people working on full case flow and paying 40 licenses for safety database (while the usage of safety database is not 100% in the whole case flow), it might be more practical for the company to divide the case flow into different steps handled by different, smaller groups (even considering vendor solution), so as to maximize the amount of report pieces handled per person and to maximize the use of safety database for the licenses paid. In that case, how to allow personnel to decide the correct reporting route and to communicate case information across steps/groups correctly and efficiently, would be a very important question to solve.

End of Case Flow and Further Activities

A case flow is literally ended at reporting step. However, for each case, the company’s evaluation does not just end there. Each single case entering the safety database can contribute to a part of the company’s continuous signal detection. With appropriate statistical methods and analytical tools, the company can identify potential signals, validate and confirm them, analyse and assess. This process is signal management, aimed to find out if there are new risks associated with the drug or whether known risks have changed. A company can refer to the Good Pharmacovigilance Practices (GVP) Module IX for guidance about signal management. Once a new risk or a change in known risk is identified, the company should evaluate if the benefit/risk balance is affected, and decide further actions, such as safety communication and label update for safety information, as necessary. Those who are interested can look up at GVP Module V, Risk Management Systems and GVP Module XV – Safety Communication for more details.