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Chapter: Pharmacovigilance: Periodic Safety Update Reports

PSURs contain proprietary information, so the title page should contain a statement on the confidentiality of the data and conclusions included in the report.


The amendment to ICH E2C stipulates that the MAH should submit a PSUR to the competent authority of the country or region in question with succinct summary information and a benefit–risk analysis in the light of new or changing post-authorisation infor-mation. Specifically, the contents of the PSUR should be as laid out in Table 6.1. The rest of this section describes an overview of a model PSUR.


PSURs contain proprietary information, so the title page should contain a statement on the confidentiality of the data and conclusions included in the report.


The executive summary should consist of a brief overview providing the reader with a description of the most important information. An example can be found on page 333 of the CIOMS V report (CIOMS, 2001).


The introduction sets the scene and puts the report in context, cross-referencing it to previous reports, describing those products/formulations that are included and excluded, outlining the pharmacology of the product, its indications (both marketed and in clinical trials) and any co-licensing agreements.


The PSUR should include a short summary of the worldwide marketing authorisation status and cross-reference this to an appendix in which the cumulative approvals (and renewal dates) should be tabulated in chronological sequence. This table should also include lack of approval, relevant explanations from regula-tory authorities and withdrawals by the company for efficacy or safety reasons.


The update on regulatory authority or MAH actions taken for safety reasons refers to

marketing authorisation, withdrawal or suspension;

failure to obtain a marketing authorisation renewal;

restrictions on distribution;

clinical trial suspension;

dosage modification/formulation changes and

changes in target population or indications.

The update should discuss the safety-related reasons that led to the actions described and append the appropriate documentation including any communica-tion with healthcare professionals (e.g. ‘Dear Doctor’ letters).


The changes in reference safety information section refers to changes in the CCSI. The CCDS, which incorporates the CCSI, should be included as an appendix. If no CCDS is available, a national SPC can be used. A covering letter should discuss meaningful differences between the CCSI and local datasheets and comment on the consequences for safety evaluations and for actions proposed or initiated.


Patient exposure refers to both market exposure and clinical trials (if relevant). Estimates of patient expo-sure for marketed drugs often rely on gross approxi-mations of in-house or purchased sales data or volume. This information is not always reliable or available for all products. For example, hospital-based statistics from the major use-monitoring sources are frequently unavailable. It is also difficult to obtain accurate data for generics, non-prescription drugs or multiple drug regimens. The MAH should use a consistent method of calculation across PSURs for the same product. If a change in the method is appropriate, both previ-ous and current methods and calculations should be shown in the PSUR introducing the change. When exposure data are based on information from a period that does not fully cover the period of the PSUR, the MAH can make extrapolations using the available data. When this is done, it should be clearly indicated what data were used and why it is valid to extrapolate for the PSUR period in question (for example stable sales over a long period and seasonality of use of the product). The CIOMS V report contains examples of patient exposure estimations (CIOMS, 2001).


There is no specific guidance in E2C on the presentation of individual case histories, but because it is impractical to present all case reports for the reporting period, a brief description of the crite-ria used to select cases for presentation should be given. This section of the PSUR should contain a description and analysis of selected cases, including fatalities, presenting new and relevant safety infor-mation and grouped by medically relevant head-ings or system organ classes (SOCs). Depending on their type or source, available ADR cases should be presented as line listings and/or as summary tabu-lations. A line listing provides key information but not necessarily all the details customarily collected on individual cases. However, it does serve to help regulatory authorities identify cases which they might wish to examine more closely by requesting full case reports. In addition to individual case line listings, summary tabulations of ADR terms for signs, symp-toms and diagnoses across all patients should usually be presented. Such tabulations should be based on the data in line listings (e.g. all serious ADRs and all non-serious unlisted ADRs) but also on other sources for which line listings are not requested (e.g. non-serious listed ADRs).


Studies refer to only those company-sponsored studies and published safety studies, including epidemiology studies, that produce findings with potential impact on product safety information. These should be included along with a discussion of any final or interim results. The MAH should not routinely catalogue or describe all the studies.


Other information may include risk management programmes the MAH has put in place and/or a benefit–risk analysis report. If such an analysis has been conducted separately, a summary of the anal-ysis should be included in this section. This section can also include important information received after the DLP, e.g. significant follow-up on cases included in the PSUR and changes to the CCSI agreed after the DLP.


The overall safety evaluation should highlight new information on serious and non-serious unlisted ADRs. For listed ADRs, it should describe any reported changes in the characteristics of the reaction (e.g. severity, outcome and target population) as well as increases in frequency of reporting of reactions. For emerging safety issues, the information received during the period under review should be discussed from the perspective of cumulative experience. For new safety issues, the current action should be stated (e.g. under active review). If there are no new safety issues, this should be stated with a note that the information is in keeping with the established safety profile. All evaluations should be concise, and the discussion and analysis should be organised by SOC rather than by listedness or seriousness. Although related terms might be found in different SOCs, they should be reviewed together for clinical relevance. This section should also review reports of

·    drug interactions;

·    overdose: deliberate or accidental and treatment;

·    abuse or misuse;

·    pregnancy or lactation: positive and negative expe-riences;

·    special patient groups (e.g. children, elderly, organ impaired) and

·    effects of long-term treatment.


The conclusion should indicate safety data which are not in accordance with previous experience and/or with the CCSI and specify and justify any action recommended or initiated.


Although the intent of the PSUR initiative is to have a standard PSUR format and content, individual coun-tries may require additional information. For example, the PSUR is designed to contain information reported or confirmed by a healthcare professional, but regula-tory agencies in some countries, including the US, also require consumer reports of ADRs. This is accom-modated by including consumer information in an Appendix to the PSUR.

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