ANNEX III U.K.SAFETY REPORTING

2. REPORTING OF SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) BY THE SPONSOR TO THE AGENCY IN ACCORDANCE WITH ARTICLE 42 U.K.

2.2. Expectedness, unexpectedness and the RSI U.K.

5. In determining whether an adverse event is unexpected, consideration shall be given to whether the event adds significant information on the specificity, increase of occurrence, or severity of a known, already documented serious adverse reaction. U.K.

6. The expectedness of an adverse reaction shall be set out by the sponsor in the RSI. Expectedness shall be determined on the basis of events previously observed with the active substance and not on the basis of the anticipated pharmacological properties of a medicinal product or events related to the subject's disease. U.K.

7. The RSI shall be contained in the SmPC or the IB. The covering letter shall refer to the location of the RSI in the application dossier. If the investigational medicinal product is authorised in several Member States concerned with different SmPCs, the sponsor shall select the most appropriate SmPC, with reference to subject safety, as the RSI. U.K.

8. The RSI may change during the conduct of a clinical trial. For the purpose of reporting SUSARs the version of the RSI at the moment of occurrence of the SUSAR shall apply. Thus, a change of the RSI impacts on the number of adverse reactions to be reported as SUSARs. Regarding the applicable RSI for the purpose of the annual safety report, see section 3 of this Annex. U.K.

9. If information on expectedness has been provided by the reporting investigator, this shall be taken into consideration by the sponsor. U.K.