The underlying principles of CIOMS II periodic safety updates were that they should be prepared to standard criteria that are practical and achievable, while containing sufficient information to reassure regulators that the data are regularly reviewed. They should be as brief as possible; it was recommended that the narrative content should not exceed about 10 pages. Data for all formulations of the same drug (including combination products) should be included in one report and the same report should be submitted at the same time to all regulatory authorities with a requirement for safety updates.
The proposal was that the guidelines should be applied to safety summaries produced for all new chemical entities licensed for the first time in 1992. Subsequent updates would be based on six-month interval data with cumulative data only included where it gave a perspective on safety issues. Each subject drug would have an international birth date (IBD), the first approval date for the first formulation of the drug anywhere in the world, that would determine the date at which six-monthly reports commenced. A data-lock point (DLP) six months after the IBD would be used to "freeze" the database. Normally, the manufacturer should make the report available within 45 calendar days of the DLP.
It should be emphasised that periodic safety summaries were not intended for the first communication of urgent safety information. This should be reported separately in the usual expedited manner.
The working group proposed that the periodic safety update was presented in nine sections as follows:
2. Core data sheet—the reference document for determining "expectedness"
3. The drug's licensed status
4. Update on regulatory or manufacturer actions taken for safety reasons
5. Patient exposure
6. Individual case histories (CIOMS line listing)
— newly analysed studies containing important safety information
— targeted new safety studies
— published safety studies
8. Overall safety evaluation
It was proposed that the individual case histories received during the six-month period of review, and meeting specified criteria, should be presented in body system order of the most serious presenting sign or symptom, in a CIOMS line-listing format. The criteria for case inclusion were as follows:
* Unlabelled, serious attributable cases from studies (published or unpublished)
* All serious and non-serious unlabelled spontaneous reports (including relevant medically unconfirmed consumer reports)
* Serious published case histories
* Serious cases from other sources (e.g. from regulatory authorities)
The CIOMS line listing should consist of:
* Company reference number
* Country of origin of report
* Source of report (e.g. physician, literature)
* Age of patient
* Sex of patient
* Dose of drug
* Duration of treatment prior to event (time to onset)
* Description of reaction (as reported)
A comment column was also suggested for use by the manufacturer to highlight important case information such as concurrent medication or underlying disease. It could also be used for the causality assessments (imputability) required by the French regulatory authority.
The overall safety evaluation should be a concise critical analysis and opinion explicitly including:
* Increased frequency of known toxicity
* Drug interactions
* Overdose and its treatment
• Positive and negative experiences during pregnancy and lactation m Effects of long-term treatment m Any specific safety issues relating to the treatment of special patient groups (e.g. elderly, children)
Finally, the evaluation should indicate whether the interim safety data remained in line with the cumulative experience to date or whether any modifications were necessary to the company's core safety information.
The CIOMS II report was published in 1992 (CIOMS, 1992).
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