The report is divided into the following five main subject areas:

* Sources of individual case reports

* Good case management practices

• Good summary reporting practices: periodic safety update reports (PSURs) reconsidered

• Population exposure data

• World-wide clinical safety reporting regulations

It is not the intention to review the details of all the topics in this chapter but some of the recommendations and guidelines are of particular interest and will be highlighted for the reader.

Sources of Individual Case Reports

Consumer Reports

The value of consumer reports has always been a point of issue between Europe and North America. The CIOMS V consensus was that it is the quality of the report and not the quality of the reporter that is important. It was agreed that medical confirmation should be sought for consumer reports and that it is important to distinguish between verification (i.e. that the events as related by the consumer occurred) and confirmation of a suspected ADR (i.e. attribution). It may even be appropriate to submit a consumer report to the regulatory authorities as an expedited report when medical confirmation is not obtainable if the case might influence the benefit-risk relationship or has implications for labelling changes.


Companies should routinely search at least two internationally recognised databases for case reports not less frequently than monthly. The clock-start date for reporting is the date the reference was identified. If the paper is not in English it may be appropriate to translate the abstract or relevant sections only. Automated searches should be supplemented to include publications relevant to the drug or circumstances. That is, it is not adequate to search only for references specific to a particular drug (e.g. salbutamol) when class review may be appropriate (e.g. beta2 agonists). It was not considered necessary to monitor the lay media but if information is made available on a case, then attempts should be made to ascertain details.


It was not considered necessary to surf the internet beyond the company's own site(s) but it is advisable to screen the latter daily for ADR reports. There was also a suggestion that it may be useful to visit known sites from which patients may obtain information on specific drugs and diseases. There was some concern over the validity of case reports posted here, since the reporter may not always be identifiable. It was agreed that if the site is secure the company could encourage ADR reporting via its "home page''. This could be used to advantage in gathering good quality data by ensuring that some fields were made mandatory for completion.

Solicited Reports

Patient support programmes are frequently being used by pharmaceutical companies to obtain follow-up data on product use (e.g. smoking cessation help lines). During the course of conversation the patient may mention the occurrence of an adverse event. It was agreed that the source of this report is neither truly spontaneous nor from a clinical trial. An additional case source, the solicited report, was proposed. It was suggested that these cases be collected and processed separately and that a company causality assessment is required before expedited reporting of serious solicited reports.

Disease-Specific Registries and Other Databases

As there are a large number of external databases it is unreasonable to expect companies to review them for ad hoc signals. However, they should be pro-actively monitored when there are known specific problems (i.e. when there is a hypothesis). As databases are used to generate signals there is no need to report individual cases on an expedited basis. However, if an increased frequency of a serious ADR was determined in an epidemiology study it may be appropriate to notify the regulatory authority. Since individual case report forms are not always appropriate, CIOMS V

introduced the concept of a ''15-day letter of prompt notification".

Good Case Management Practices

Clinical Evaluation

This is important for determining any further action required to characterise a case, in particular to establish the accuracy of the diagnosis and appropriate coding. It also enables the case to be suitably prioritised for follow-up and/or expedited reporting. It was recognised that many companies are coding every event of which they become aware, even if not causally related to the drug. The concept of an ''incidental event'' was introduced. This is an event which, although it occurs in reasonable temporal association with the use of a drug, is not the intended subject of a spontaneous report and there is no implicit or explicit expression of possible drug causality by the reporter or the company. Cases in which only the incidental events are serious should not be submitted as expedited reports.


CIOMS V recommended the universal adoption of the ICH E2A definition of seriousness, including medically important events. For consistency it was suggested that all companies maintain a list of terms which should always be considered serious. However, it was recognised that this could never be fully comprehensive and that it does not replace medical judgement.

Cases with a fatal outcome are only serious when the ADR is a direct or indirect cause of death.


Events are only expected when they are included in the ADR section of the reference safety information (RSI). If they differ in nature, severity, specificity or outcome, then they are unexpected. Class labelling and statements such as ''relationship not established'' or ''observed with similar frequency to placebo'' do not imply expectedness.

Principles of Reporting Deaths

This was perhaps the most contentious of all the discussions. Some regulators considered that they needed to know about all reports of deaths, while manufacturers generally maintained that they would be swamped with reports, especially for drugs used in serious medical conditions. It was upheld that cases with a fatal outcome were only serious when the drug caused or contributed to death but there was general disagreement about whether this could always be determined from individual case details, or implied if the case was a spontaneous report. Further discussion centred on whether death was considered expected or unexpected if it was not specifically mentioned in the label (e.g. "anaphylaxis" versus "anaphylaxis, sometimes fatal''). It was agreed that physicians should be aware of medical conditions frequently associated with a fatal outcome and therefore the working group decided actively to discourage indiscriminate labelling of deaths. The final outcome of this discussion was to recommend that fatal reports should be expedited until labelled and that all reports with a fatal outcome should undergo special medical review.


Guidance is given on prioritising cases for follow-up, the highest priority being given to all serious cases; unexpected cases; special interest cases and those which are uninterpretable in order to seek clarification. As always, the topic of whether cases should be followed to resolution was raised as there was concern that a non-serious rash, for example, may become Stevens-Johnson Syndrome. It was suggested that when a letter of acknowledgement was sent, as is good practice, the reporter should be asked to notify the company if any further information becomes available on the case.

Good Summary Reporting Practices: PSURs

Whilst agreeing that the full ICH E2C format PSUR should be produced every six months for most drugs, the working group recognised that this presents a number of practical difficulties in terms of format and content. At one extreme, there are high volume reports that may contain thousands of ADR case reports or an unmanageable volume of publications. At the other extreme, there are older drugs with a well-established profile for which there is little or no new information to report. Modifications to PSUR content are proposed for the former high volume reports and recommendations for simplifying reports, with an example, are given for the latter. It is emphasised that the working group is not suggesting new format reports but simply offering pragmatic suggestions for adapting the ICH E2C content and format in certain circumstances.

One of the greatest dilemmas in producing PSURs is fulfilling the different frequency and periodicity requirements for different regulatory authorities in different countries. For example, in Europe, the schedule for submission changes to annual after two years and then five-yearly after the first renewal. Under ICH E2C provisions, regulators who do not wish to receive six-monthly reports are expected to accept two six-monthly reports as an annual report or the appropriate series of reports as a five-year report. The working group therefore proposed the use of the summary bridging report to facilitate the review of a series of reports. The summary bridging report is a concise document integrating the information presented in two or more PSURs that is submitted to a regulatory authority to cover a specified period over which a single report is required. An example is presented in the final report.

The concept and use of the IBD for PSURs have not been fully accepted by all regulators. Some require that PSURs are scheduled according to the local approval date and, in addition, not all companies will have synchronised their renewal dates by bringing them forward to the IBD in those countries where this is permissible. To avoid producing additional reports for those countries perceiving that any report with a DLP more than 60 days before submission is out of date, the working group recommended the use of an addendum report. This is an update to the most recently completed scheduled PSUR when a regulatory authority (or the company) requires a safety update outside the usual reporting cycle, and more than a brief amount of time has elapsed since the most recent PSUR. The working group proposed the minimum information for inclusion in the addendum report.

Finally, other issues of practical importance in managing the preparation of PSURs that are not directly related to format and frequency are discussed. Many of these topics were issues raised in a survey undertaken by the working group to identify the current PSUR burden to industry.

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