Can we win a Nobel Prize with a CSR?

Update on the post from Oct 27, 2006

The discussion regarding Safety Narratives in Clinical Study Reports is still ongoing. There are still some open question, the most important being: Does chapter 12.2.2 of the ICH E3 Guideline require an interpretative narrative, i.e. an assessment of each individual Adverse Event, similar to those in the CIOMS form?

This question boils down to the interpretation of section 12.3.2 and 12.3.3. According to my opinion, which is supported by some colleagues, it is sufficient to include a non-interpretative narrative in 12.3.2 and to have all interpretation in section 12.3.3.

In addition, the following questions also need to be addressed:

• Is a review required, when the process for creating auto-generated narratives is validated?


• Are all items to become part of the auto-generated narrative to be reconciled?

Here is the original text from the ICH E3 Guideline:

12.3.2 Narratives of Deaths, Other Serious Adverse Events and Certain Other Significant Adverse Events
There should be brief narratives describing each death, each other serious adverse event, and those of the other significant adverse events that are judged to be of special interest because of clinical importance. These narratives can be placed either in the text of the report or in section 14.3.3, depending on their number. Events that were clearly unrelated to the test drug/investigational product may be omitted or described very briefly. In general, the narrative should describe the following: the nature and intensity of event, the clinical course leading up to event, with an indication of timing relevant to test drug/investigational product administration; relevant laboratory measurements, whether the drug was stopped, and when; countermeasures; post mortem findings; investigator's opinion on causality, and sponsor's opinion on causality, if appropriate.
In addition, the following information should be included:

• Patient identifier


• Age and sex of patient; general clinical condition of patient, if appropriate


• Disease being treated (if the same for all patients this is not required) with duration (of current episode) of illness


• Relevant concomitant/previous illnesses with details of occurrence/duration


• Relevant concomitant/previous medication with details of dosage


• Test drug/investigational product administered, drug dose, if this varied among patients, and length of time administered

12.3.3 Analysis and Discussion of Deaths, Other Serious Adverse Events and Other Significant Adverse Events
The significance of the deaths, other serious adverse events and other significant adverse events leading to withdrawal, dose reduction or institution of concomitant therapy should be assessed with respect to the safety of the test drug/investigational product. Particular attention should be paid to whether any of these events may represent a previously unsuspected important adverse effect of the test drug/investigational product. For serious adverse events that appear of particular importance, it may be useful to use life table or similar analyses to show their relation to time on test drug/investigational product and to assess their risk over time.