Regulation (EU) No 536/2014 of the European Parliament and of the CouncilDangos y teitl llawn

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

2.1. Adverse Events and Causality U.K.

2. Medication errors, pregnancies and uses outside what is foreseen in the protocol, including misuse and abuse of the product, shall be subject to the same obligation to report as adverse reactions. U.K.

3. In determining whether an adverse event is an adverse reaction, consideration shall be given to whether there is a reasonable possibility of establishing a causal relationship between the event and the investigational medicinal product based on an analysis of available evidence. U.K.

4. In the absence of information on causality provided by the reporting investigator, the sponsor shall consult the reporting investigator and encourage him to express an opinion on this issue. The causality assessment given by the investigator shall not be downgraded by the sponsor. If the sponsor disagrees with the investigator's causality assessment, the opinion of both the investigator and the sponsor shall be provided with the report. 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.

2.3. Information for the reporting of SUSARs U.K.

10. The information shall at least include: U.K.

(a)

a valid EU trial number;

(b)

a sponsor study number;

(c)

an identifiable coded subject;

(d)

an identifiable reporter;

(e)

a SUSAR;

(f)

a suspect investigational medicinal product (including active substance name-code);

(g)

a causality assessment.

11. In addition, in order to properly process the report electronically, the following administrative information shall be provided: U.K.

(a)

the sender's (case) safety report unique identifier;

(b)

the receive date of the initial information from the primary source;

(c)

the receipt date of the most recent information;

(d)

the worldwide unique case identification number;

(e)

the sender identifier.

2.4. Follow-up reports of SUSARs U.K.

12. If the initial report of a SUSAR referred to in point (a) of Article 42(2) (fatal or life-threatening) is incomplete, for example if the sponsor has not provided all the information within seven days, the sponsor shall submit a completed report based on the initial information within an additional eight days. U.K.

13. The clock for initial reporting (day 0 = Di 0) starts as soon as the information containing the minimum reporting criteria has been received by the sponsor. U.K.

14. If significant new information on an already reported case is received by the sponsor, the clock starts again at day zero, that is the date of receipt of the new information. This information shall be reported as a follow-up report within 15 days. U.K.

15. If the initial report of a SUSAR referred to in Article 42(2)(c) (initially considered to be non-fatal or non-life-threatening but which turns out to be fatal or life-threatening) is incomplete, a follow-up report shall be made as soon as possible, but within a maximum of seven days of first knowledge of the reaction being fatal or life-threatening. The sponsor shall submit a completed report within an additional eight days. U.K.

16. In cases where a SUSAR turns out to be fatal or life-threatening, whereas initially it was considered as non-fatal or not life-threatening, if the initial report has not yet been submitted, a combined report shall be created. U.K.

2.5. Unblinding treatment allocation U.K.

17. The investigator shall only unblind the treatment allocation of a subject in the course of a clinical trial if unblinding is relevant to the safety of the subject. U.K.

18. When reporting a SUSAR to the Agency, the sponsor shall only unblind the treatment allocation of the affected subject to whom the SUSAR relates. U.K.

19. If an event is potentially a SUSAR the blind shall be broken for that subject only by the sponsor. The blind shall be maintained for other persons responsible for the ongoing conduct of the clinical trial (such as the management, monitors, investigators) and those persons responsible for data analysis and interpretation of results at the conclusion of the clinical trial, such as biometrics personnel. U.K.

20. Unblinded information shall be accessible only to persons who need to be involved in the safety reporting to the Agency, to Data Safety Monitoring Boards (’DSMB’), or to persons performing ongoing safety evaluations during the clinical trial. U.K.

21. However, for clinial trials carried out in high morbidity or high mortality disease, where efficacy end-points could also be SUSARs or when mortality or another ’serious’ outcome, that may potentially be reported as a SUSAR, is the efficacy end-point in a clinical trial, the integrity of the clinical trial may be compromised if the blind is systematically broken. Under these and similar circumstances, the sponsor shall highlight in the protocol which serious events are to be treated as disease-related and are not subject to systematic unblinding and expedited reporting. U.K.

22. If following unblinding, an event turns out to be a SUSAR the reporting rules for SUSARs set out in Article 42 and in Section 2 of this Annex shall apply. U.K.