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AE/SAE Reporting Guidelines Background It is a legal requirement under clinical trial regulations, which implement the EU Clinical Trials Directive 2001/20/EC into law, to record and report adverse events (AEs), Adverse Reactions (ARs), Serious Adverse Events (SAEs), Serious Adverse Reactions (SARs) and Suspected Unexpected Serious Adverse Reactions (SUSARs) that occur in patients participating in Clinical Trials of Investigational Medicinal Products (CTIMPs). Scope These guidelines apply to the site Principal Investigator (PI) and all site staff who have been delegated the task of recording and reporting AEs/SAEs. Responsibilities of the Clinical Research Support Centre (CRSC) The CRSC acting on behalf of the Sponsors have been delegated responsibility for pharmacovigilance. The CRSC is responsible for keeping records of AEs and SAEs that occur in trial patients as per the protocol and reporting SAEs and SUSARs to the Sponsors, Ethics and Regulatory Agencies within the required timelines as per the regulatory requirements. The CRSC will undertake a review of AE/SAE related documents at each site during monitoring visits to ensure that all relevant documents are completed, filed and have been reported as per the protocol and the regulatory requirements. Responsibilities of the Principal Investigator (PI) The PI may delegate AE and SAE recording and reporting responsibilities to medically qualified persons who can cover in their absence. The delegation of tasks should be documented in the Delegation Log (Doc No: TM01-RD04) which must be held in the Investigator Site File (ISF). Delegation Logs should be faxed to the CRSC as any updates to staff and tasks delegated occur. This will enable the CRSC to verify signatures on SAE forms and check that only staff who have been delegated SAE reporting responsibilities have completed the forms, and only those that have been delegated responsibility in the absence of the PI signs SAE Forms. The PI is responsible for keeping records of AEs and SAEs that occur in trial patients as per the protocol and as outlined below. Adverse Event Reporting Assess each AE for seriousness, causality and expectedness (Appendix 1). The following documents should be at hand when assessing any AE in the trial; Protocol and Summary of Product Characteristics (SmPC). Because HARP-2 is recruiting a population that is already in a life-threatening situation, it is expected that many of the participants will experience AEs. Events that are expected in this population (i.e. events that are in keeping with the patient’s underlying medical condition) should not be reported. An adverse reaction (AR) is an AE which is related to the administration of the study drug. If any AEs are related to the study drug (i.e. are ARs) they must be reported. The following are ARs which are expected and must be reported: Creatinine Kinase > 10 times the upper limit of normal Alanine Aminotransferase (ALT) > 8 times the upper limit of normal Aspartate Aminotransferase (AST) > 8 times the upper limit of normal The PI needs to enter the details relating to ARs in the medical records of the patient and on the AE Form of the Case Report Form (CRF). Submit the AE Form along with the other sections of the CRF to the CRSC as per the CRF Submission Guidelines. ARs do not require expedited reporting. The data manager will review the AE Form and raise queries for the site as deemed necessary, eg. if an AR is not resolved at the time of reporting. HARP-2 Page 1 of 3 AE/SAE Reporting Guidelines_v2.0 Final_ 29/03/12 AE/SAE Reporting Guidelines Serious Adverse Event Reporting Assess each AE for seriousness, causality and expectedness (Appendix 1). The following documents should be at hand when assessing any AE in the trial; Protocol and Summary of Product Characteristics (SmPC). Because HARP-2 is recruiting a population that is already in a life-threatening situation, it is expected that many of the participants will experience SAEs. Events that are expected in this population (i.e. events that are in keeping with the patient’s underlying medical condition) and that are collected as outcomes of the trial, including death and organ failure should not be reported as SAEs. Other SAEs must be reporte A serious adverse reaction (SAR) is an SAE which is related to the administration of the study drug. If any of the above are related to the study drug (i.e. are SARs) they must be reported. The following SAR is expected and must be reported: Need for renal replacement therapy in patients with Creatinine Kinase > 10 times the upper limit of normal. The PI needs to enter the details relating to SAEs and SARs in the medical records of the patient, the AE Form within the CRF, the Serious Adverse Event Log (Doc No: TM02-RD05) and the SAE Form within the CRF. SAEs require expedited reporting. Submit the SAE Form in the CRF to the CRSC within 24 hours of first becoming aware of the event. The SAE Form should be faxed to the CRSC along with a Notification of SAE form to: Fax Number: 0044 (0)28 9063 3554 The SAE Form should be as complete as possible and must be signed and dated by the PI or delegate as documented on the Delegation Log. For instances when both the PI and delegate are absent in the first 24 hours, a partially completed SAE Form should be submitted to the CRSC within 24 hours of becoming aware of the event. The completed SAE form must subsequently be reviewed by the PI or delegate and submitted to the CRSC as soon as possible. If all the required information is not available at the time of reporting, the PI must ensure that any missing information is provided as soon as this becomes available. The PI should provide this information on the SAE Follow Up Form within the CRF and fax this to the CRSC along with a Notification of SAE form. It should be indicated on the report that this information is follow up information to a previously reported event. Following the submission of a SAE Form to the CRSC the Trial Manager/Trial Coordinator will confirm receipt within 2 business days. If confirmation of receipt is not received, site staff should contact the CRSC. All SAE reports to the CRSC should be retained in the ISF, along with the Notification of SAE form and acknowledgement of receipt provided by the CRSC. The original CRF (Sections 13 and 14) should be submitted along with all other sections of the CRF within 3 months of randomisation. NOTE: If the SAE is judged to be a SUSAR, the CRSC may require additional information from the site to ensure all information required to be reported as per the regulatory requirements is captured. The Trial Manager/Trial Co-ordinator will contact the site to obtain further information as deemed necessary. HARP-2 Page 2 of 3 AE/SAE Reporting Guidelines_v2.0 Final_ 29/03/12 AE/SAE Reporting Guidelines Appendix 1 – Assessment of Adverse Events These definitions are taken from the European Union Clinical Trials Directive 2001/20/EC. Table 1 Term Adverse Event (AE) Adverse Reaction (AR) Unexpected Adverse Reaction (UAR) Serious Adverse Event (SAE) Serious Adverse Reaction (SAR) Suspected Unexpected Serious Adverse Reaction (SUSAR) Definition Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. All untoward and unintended responses to an investigational medicinal product related to any dose administered An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. investigator’s brochure for an unauthorised investigational product or summary of product characteristics for an authorised product). Respectively, any adverse event, adverse reaction or unexpected adverse reaction that: a) results in death; b) is life-threatening; c) requires hospitalisation or prolongation of existing hospitalisation; d) results in persistent or significant disability or incapacity; e) is a congenital anomaly or birth defect; f) is any other important medical event(s) that carries a real, not hypothetical, risk of one of the outcomes above Assessment of Seriousness Each AE should be assessed for seriousness as per the definition of a SAE in Table 1 above. Assessment of Causality Each AE should be clinically assessed for causality, i.e. the relationship of the AE to the study drug. For the purposes of this trial the causality should be assessed using the categories presented below. Drug related AEs are defined as those considered by the PI to have a possible, probable or definite relationship to the study drug. Unrelated – clinical event with an incompatible time relationship to study drug administration, and that could be explained by underlying disease, or other drugs or chemicals Unlikely – clinical event whose time relationship to study drug administration makes a causal connection improbable, but that could plausibly be explained by underlying disease or other drugs or chemicals Possible – clinical event with reasonable time relationship to study drug administration, but that could also be explained by concurrent disease or other drugs or chemicals Probable – clinical event with a reasonable time relationship to study drug administration, and is unlikely to be attributed to concurrent disease or other drugs or chemicals Definite – clinical event with plausible time relationship to study drug administration, and that cannot be explained by concurrent disease or other drugs or chemicals Assessment of Expectedness Each AE should be assessed as to whether it was expected or not. If an AE is judged to be related to the study drug, the PI is required to make an assessment of expectedness based on knowledge of the AR and any relevant product information as documented in the Summary of Product Characteristics (SmPC). HARP-2 Page 3 of 3 AE/SAE Reporting Guidelines_v2.0 Final_ 29/03/12