CIOMS III - Core Clinical Safety Information

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Chapter: Pharmacovigilance: CIOMS Working Groups and their Contribution to Pharmacovigilance

MS II introduced the concept of the core data sheet. It is a document prepared by the pharmaceutical manufacturer, containing the minimum essential safety information.



CIOMS II introduced the concept of the core data sheet. It is a document prepared by the pharmaceutical manufacturer, containing the minimum essential safety information, such as ADRs, which the manufacturer stipulates should be listed in all coun-tries where the drug is marketed (see Figure 23.3). It is also the reference document by which ‘labelled’ and ‘unlabelled’ (or listedness and unlistedness for ICH E2C) are determined. Thus, it should focus on the important information required for rational clinical decision-making and harmonise safety state-ments worldwide for public health and regulatory purposes.

The CIOMS III working group set out to propose principles and guidelines for consistent decision-rules on the content of the Core Safety Information (CSI), standard terms and definitions, and a standard format. One of the major concerns was to minimise confusion among prescribers and other healthcare professionals due to inconsistencies between the safety informa-tion presented in different countries and by different manufacturers.

It was therefore hoped that regulatory authori-ties would harmonise their basic requirements for safety information in their local data sheets. However, the working group acknowledged the possible need for cultural differences due to medical and legal differences.

The first edition of the CIOMS III report published in 1995 (CIOMS, 1995) focused on CSI for marketed products, including the initial CSI that is prepared in conjunction with the first market autho-risation submission, review and approval. During CIOMS V discussions it was proposed that the same basic philosophy and practices be applied to the safety information provided to clinical investiga-tors during a development programme. The concept of development core safety information (DCSI) as a discrete, focused section of the Investigator’s Brochures, which would have the same format as, and would evolve into, the CSI at initial marketing of the product, was therefore agreed. A second edition of the CIOMS III report was issued in 1999 (CIOMS, 1999) including the new proposals for Investigator’s Brochures.


The task of the working group was to develop propos-als for standard principles and guidelines addressing the what, when, how and where of CSI. The summary of product characteristics (SPC), the official document of the European Union, was used as a model to try to answer the following general questions:

What evidence is needed, and how should it be used, to influence a decision on whether an adverse experience should be included, excluded or removed from the CSI?

At what point in the accumulation and interpre-tation of information is the threshold crossed for inclusion or change in the CSI?

What ‘good safety-labelling practices’ can be spec-ified concerning the clinical relevance of informa-tion, how it is expressed and the appropriateness of ‘class-labelling’?

What should the sections of the CSI be called, how should they be defined and where should specific information be located?

At the beginning of the process the group hoped to develop specific threshold criteria, or an algorithm, for determining when information should be included in the CSI. However, this was not possible and it became necessary to rely on collective judgement to reach consensus. A series of case scenarios were created from real-life examples for which the decision to amend a data sheet was equivocal. Each member of the group was asked individually to make decisions on the available data. In addition, each person was asked to list the factors taken into consideration when reaching their conclusions. A total of 39 factors were identified and each member of the working group was asked to rank the factors in order of importance. As expected, there was a considerable divergence of opinion but overall the mostly highly ranked criterion for a positive decision was the presence of positive rechallenge information. The reader is referred to the original report for the remaining factors and their respective rankings.


The working group formulated a total of 65 propos-als relating to general principles of good safety information and the what, when, how, where and who (responsibilities) for CSIs. A selection of the most useful principles is given below.


The CSI should be determined by the needs of healthcare professionals in the context of a regula-tory and legal environment.

Include what is practical and important to enable the prescriber to balance risks against benefit and to act accordingly.

Avoid including events, especially minor events, that have no well-established relationship to therapy.

There is a legal duty to warn but this must be balanced against the need to include only substan-tiated conclusions in the CSI.

The CSI should include important information which physicians are not generally expected to know. (The converse is also true.)


As soon as relevant safety information becomes sufficiently well established it should be included in the CSI.

It was not possible to define this more precisely but the working group introduced the concept of ‘thresh-old’. This is dependent on the quality of information available and the body and strength of the evidence according to the 39 criteria (plus two additional ones subsequently identified) in the ranking exercise described above. Situations in which the threshold should be lowered were identified. In general, infor-mation should be added sooner whenever it is likely to help the physician make a differential diagnosis related to an adverse event, spare extra tests, lead to the use of a specific targeted test or facilitate early recognition of an event. Similarly, the thresh-old should also be lowered if the ADR is medically serious or irreversible, if good alternative drugs are available, a relatively trivial condition is being treated, or the drug is being used for prophylaxis.


Keep ADRs identified in the initial CSI (pre-marketing experience) separate from those identi-fied subsequently.

ADRs should be listed by frequency in body system order.

Whenever possible, an estimate of frequency should be provided, expressed in a standard cate-gory of frequency.

While the working group recognised that precise frequency rates can only be obtained from studies and are limited to the more common reactions, it was agreed that estimates of frequency in a standard format should be provided whenever possible. Although it is difficult to estimate incidence on the basis of spon-taneous reports due to the uncertainties in estimating denominator and the degree of under-reporting, the group recommended the standard frequencies shown in Table 23.3.

Finally, the working group defined the safety sections of the CSI, providing guidance on the infor-mation which should be included in each section and outlined the responsibilities of the company for remaining diligent and proactive, including undertak-ing the scientific investigation of signals. The shared responsibility of healthcare providers, patients, editors of medical journals and regulators is also addressed.


Since the standards proposed by the CIOMS III working group would require continuous evaluation, updating and refinement, it was suggested that they be retained as guidelines and not adopted as regu-lations. They have been used as the basis of the European Labelling Guidelines and many regulatory authorities have adopted the standard categories of frequency. However, during the most recent redraft-ing of the European Labelling Guidelines there was discussion regarding their appropriateness when spon-taneous reports are the only source of data for esti-mating frequency.

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