Document Title: Adverse Event Reporting

Document Title: Adverse Event Reporting Document Number: SOP012 Staff involved in development: Job titles only Document author/owner: Directorate: Department: For use by: RM&G Manager, R&D Administration Manager, Research Officers R&D Administration Manager Research and Development Research and Development NHS Staff Trust-Wide Review due: April 2016 THIS IS A CONTROLLED DOCUMENT Whilst this document may be printed, the electronic version maintained on the Trust s Intranet is the controlled copy. Any printed copies of this document are not controlled. Papworth Hospital NHS Foundation Trust. Not to be reproduced without written permission. Key Points of this Document This document sets out the procedures to be followed by all Papworth Staff who are involved in the reporting of adverse events in clinical trials. It aims to provide clear guidance on how to report adverse events and incidents that occur in the course of research studies to ensure compliance with the Trust s policy for the reporting of accidents / adverse events / incidents and defects (DN70). Version 3.2 Review Date: April 2016 Page 1 of 16

1 Purpose and Content a. This document defines the Trust s research procedures for the reporting and investigation of any adverse event that occur involving patients in Research Studies and Clinical Trials sponsored by Papworth Hospital s R&D department. This includes the completion of Adverse Event forms. b. In accordance with the Research Governance Framework for Health and Social Care and the Medicines for Human Use (Clinical Trials) Regulations, organisations hosting and Sponsoring research must have systems in place that allow to give the safety of participants and of research and other staff priority at all times, and [ensure that] health and safety regulations [are] strictly observed including the provision of information, containment, shielding and monitoring as required. c. The Medicines for Human Use (Clinical Trials) Regulations 2004 came into force on the 1st May 2004. These regulations apply to all clinical trials involving investigational medicinal products (IMPs) and specify the reporting requirements for related adverse events. To breach these requirements constitutes a breach in criminal law. These reporting requirements have been incorporated within this policy. d. This SOP covers the recording and reporting of Research Related Adverse Events, including Adverse Reactions, Adverse Device Effects, Serious Adverse Events, Serious Adverse Reactions, Serious Adverse Device Effects, Suspected Unexpected Serious Adverse Reactions and Unanticipated Serious Adverse Device Effects. These adverse events will be managed in line with the reporting policy of the Sponsor of a research study. e. The reporting requirements in this SOP are mandatory in addition to the Trust s policy for the reporting of accidents / adverse events / incidents and defects (DN70) and noncompliance with may result in disciplinary procedures. 2 Roles & Responsibilities 2.1 Roles a. All staff are responsible for ensuring that all adverse incidents, whether or not related to research, are reported in accordance with the Papworth Hospital NHS Trust s policy for the reporting of accidents / adverse events / incidents and defects (DN70). b. This Procedure applies to all personnel that are conducting research at the Trust. Version 3.2 Review Date: April 2016 Page 2 of 16

c. Staff involved in the conduct of CTIMPs must comply with the requirements set out in this SOP. d. Flow diagrams that summarise the investigator s and sponsor s responsibilities for reporting adverse events are available from the Papworth R&D department. 2.2 Investigators responsibilities a. The investigator must ensure that the dignity, rights, safety and well being of research participants are given priority at all times and must take appropriate action to ensure the safety of all staff and participants in the study. The investigator will consider what actions, if any, are required and in what timeframe following the requirements set in this policy. b. In the event of an adverse event / reaction (AEs) the investigator (or delegate) must review all the documentation that is relevant to the event (e.g. patient notes, laboratory reports). The event and relevant comments must be recorded in the subject s medical notes (or source data) and reported to the Sponsor as documented in the protocol. Investigators (or delegated persons) will provide follow-up information, each time new information is available using the study CRF provided or page 3 of the form entitled FRM007 Papworth SAE/SUSAR Reporting Form (available from the R&D intranet pages). This will be completed until the SAE / SADE has resolved or a decision for no further follow-up has been taken by the PI or delegated person. c. Unless the protocol states otherwise and has exempted certain events from being recorded or escalated reporting, the Investigator (or delegate) is responsible for ensuring that all adverse event / reactions are recorded in detail on case report forms or equivalent so as to allow analysis at a later stage. A template for recording adverse events can be found on the R&D intranet pages entitled FRM005 Adverse Event/Adverse Reaction Reporting Form). d. The investigator (or delegate) will make an assessment of causality for all adverse event / reactions. This process must be clearly documented. This must be completed by medically qualified personnel. Detailed guidance on making this assessment is given in the Appendix 1. A short assessment for the internal purposes of the research team is provided in the form Version 3.2 Review Date: April 2016 Page 3 of 16

entitled FRM005 Adverse Event/Adverse Reaction Reporting Form. e. The Investigator (or delegate) must ensure that Adverse Events and / or laboratory abnormalities identified in the protocol as critical to the evaluations of the safety of the study shall be reported to the Sponsor in accordance with the reporting requirements documented in the protocol. f. The chief investigator will keep the Sponsor, the REC and MHRA (if applicable) informed of any significant findings and recommendations by an independent Data Monitoring Committee (DMC), or equivalent, where one has been established for the trial. 2.3 Sponsor responsibilities a. This section applies only where Papworth R&D is the sponsor or co-sponsor of the research study A flow diagram summarising the R&D department s responsibilities for adverse event reporting is available from Papworth R&D department upon request. b. The Senior Manager, or their delegated representative, must keep a detailed record of all AEs relating to all clinical trial that are reported to it and ensure that system is in place for ensuring appropriate follow-up of SAEs. On receipt of a SAE / SUSAR report form the Senior Manager will assess whether Papworth R&D is the sponsor. Where Papworth R&D is NOT the sponsor or cosponsor the Senior Manager will remind the research team to inform the sponsor. c. The Senior Manager, or their delegated representative, must ensure that cover will be provided for the fax machine used for sending in adverse event reports to ensure events are processed in a timely manner (which includes holiday periods). d. The Senior Manager, or their delegated representative, is responsible for the assessment of expectedness of adverse events. This responsibility may be delegated the chief investigator. This delegation must be clearly documented. Version 3.2 Review Date: April 2016 Page 4 of 16

2.4 For Blinded Studies: a. Where Papworth R&D is the sponsor or cosponsor of a blinded research study, in which the SAE / SUSAR / SADE / USADE has occurred, and a member of the research team is unable to make a blinded assessment, the Senior Manager, or their delegated representative, will make an unblinded assessment of the intensity, causality, expectedness and seriousness using the criteria described in this policy. b. In making this assessment the Senior Manager, or their delegated representative, will consult the independent Data Monitoring Committee (DMC) for the study or, where a DMC does not exist, a suitably qualified medical person. The unblinded assessor may be an investigator on the same study if unblinding him / her will not affect the conduct of the study in which the SAE has occurred. c. A second assessment by the Sponsor is not required where the investigator making the initial assessment is already unblinded. d. A clear procedure must be detailed in the protocol for Papworth sponsored CTIMPs. e. The Senior Manager, or their delegated representative, will consider whether any further actions following an adverse event, in addition to those already taken by the Investigator, are required and will discuss these with the Investigator. f. The Senior Manager, on behalf of the Trust, reserves the right to suspend or withdraw approval for a study. This may happen, but is not limited to, where public health and safety is considered to be at risk, where the safety and well being of research subjects or staff are considered to be at risk. g. The sponsor is responsible for ensuring that actions that necessitate a substantial amendment to the research protocol will be approved by ethical, R&D and MHRA (for IMP and non CE marked devices) through the normal routes. See SOP037 Amendments Post Trust Approval for further information. This duty may be delegated to the Chief Investigator. h. Amendments that require an immediate change to the protocol (i.e. urgent safety measures) will be implemented and thereafter submitted for ethical, R&D and MHRA approval. The initial notification to the REC should be by telephone. Notice in writing to the REC, hosting R&D and MHRA should be sent within three days. The notice should set out the reasons for the urgent safety measures and plan for further action. i. The Sponsor is responsible for ensuring that at the conclusion of the study all adverse events / reactions / device effects, recorded during a study are subject to statistical analysis and that analysis and subsequent conclusions included in the final study report. Version 3.2 Review Date: April 2016 Page 5 of 16

3 Definitions AE Adverse Event - any untoward medical occurrence in a subject to whom a medicinal product / medicinal device / intervention has been administered, including occurrences which are not necessarily caused or related to the product. AR Adverse Reaction - any untoward and unintended response in a subject to an investigational medicinal product / medicinal device / intervention that is related to any dose administered to that patient. ADE Adverse Device Event - any malfunction or deterioration in the characteristics and / or performance of a device, as well as any inadequacy in the labelling or the instructions for use that might lead, or might have led to, endangering the health of a patient or the device user. An unexpected adverse reaction is an adverse reaction the nature and severity of which is not consistent with the information about the medicinal product or intervention in question set out: in the case of a product with a marketing authorisation, in the Summary of Product Characteristics (SmPC) for that product in the case of any other investigational medicinal product, in the Investigators Brochure (IB) SAE /SADE / SAR SAE SADE An adverse event, adverse reaction, unexpected adverse reaction, adverse device effect is defined as serious if it: results in death is life-threatening requires hospitalisation or prolongation of existing hospitalisation results in persistent or significant disability or incapacity consists of a congenital anomaly or birth defect Serious Adverse Event Serious Adverse Device Event Version 3.2 Review Date: April 2016 Page 6 of 16

SAR SUSAR Serious Adverse Reaction Suspected Unexpected Serious Adverse Reaction - is an SAR that is suspected (possibly of probably) to be related to the investigational medicinal product / medicinal device / intervention AND is also unexpected. This means that its nature and severity are not consistent with the information about the medicinal product in question set out as below: in the case of a product with a marketing authorisation, in the Summary of Product Characteristics (SmPC) for that product in the case of any other investigational medicinal product, in the Investigators Brochure (IB) A non-imp SUSAR is an SAE that occurs in a non-imp trial and is: Related that is possibly, probably or definitely resulted from administration of any of the research procedures, and Unexpected that is, the type of event is not listed in the protocol as an expected occurrence USADE Unanticipated Serious Adverse Device Effect - an untoward medical occurrence that happens in a subject or other person that is related to the investigational device, device procedure or comparator, which is serious and was unanticipated. 4 Procedure If a participant is participating in a randomised clinical trial the reporting must be carried out according to this SOP irrespective of the arm of the trial the patient is in. 4.1 Reporting of Serious Adverse Events / Serious Adverse Device Effects a. Researchers must ensure that all patient safety related incidents are reported according to the Trust s policy for the reporting of accidents / adverse events / incidents and defects (DN70). b. In addition to the Trust s incident reporting, serious adverse events must be reported as per Table 1. The only exception is where the protocol or Investigators Brochure identifies an event as not requiring immediate expedited reporting. Table 1 Report to Investigator Responsibilities SUSAR / USADE Immediately report to: The investigator (or delegated person) will make an initial report, orally or in writing, within 24 hours of Version 3.2 Review Date: April 2016 Page 7 of 16

The Chief Investigator The Sponsor knowledge of the event. The initial report will include as much information as is available at the time. Papworth department R&D Oral reports will be followed up in writing within a further 24 hours of the initial report. Papworth Clinical Governance and Risk Management Any other persons or bodies specified in the protocol Sponsor responsible to further expedite the reporting of SUSAR / USADE to the MHRA and REC that gave approval as soon as possible but within 7 days of knowledge of the event. After the initial report the investigator is required to actively follow up the subject. The investigator (or delegated person) will provide information missing from the initial report within five working days of the initial report. Written reports will be made by completing an SAE / SUSAR reporting form provided by the Sponsor of the study. In addition the REC receives a completed NRES CTIMP Safety Report to REC http://www.nres.npsa.nhs.uk/applications/afterethical-review/safetyreports/safety-reports-forctimps/ Papworth R&D SAE / SAR / SUSAR report template entitled FRM007 SAE/SAR/SUSAR Reporting Form v1.0 is available from the Research Department Where Papworth is the sponsor or co-sponsor or where no form has been provided, the investigator will use the standard Research Related SAE/SUSAR form entitled FRM007 SAE/SAR/SUSAR Reporting Form v1.0 that is available from R&D. Only one report will need to be sent to Papworth R&D department. SAE / SADE Within 24 hours report to: The Chief Investigator The Sponsor Any other persons or bodies specified in the protocol As above; but no expedited reporting by the Sponsor to the MHRA and REC. Version 3.2 Review Date: April 2016 Page 8 of 16

For Papworth Sponsored CTIMPs and non-ce marked devices also contact the R&D department. Urgent Safety Measures / Temporary Halt of a Trial Implement and report immediately as a substantial amendment to: The Chief Investigator The Sponsor The Chief Investigator must inform as soon as possible, but within 3 days: The MHRA The REC that gave approval Any other persons or bodies specified in the protocol Papworth R&D department The Sponsor and the Chief Investigator must be notified of any urgent safety measures / temporary halt of a trial that have had to be taken that are not part of the protocol. The report must include the reasons for the urgent safety measure and the plan for further action. The standard CTIMP substantial amendment form must be used as available from MHRA / NRES websites. http://www.nres.npsa.nhs.uk/applications/afterethical-review/notification-of-amendments/ Where Papworth R&D is the Sponsor (or Cosponsor) and the host organisation only one report needs to be sent to the R&D department. 4.2 For Papworth Sponsored Studies a. The Chief Investigator will inform all Principal Investigators of relevant information about SAEs / SADEs that could adversely affect the safety of subjects. b. The Chief Investigator will provide the main REC with copies of all reports and recommendations of any independent Data Monitoring Committee established for a trial as part of the SUSAR / USADE expedited or periodic reporting. Version 3.2 Review Date: April 2016 Page 9 of 16

c. For IMP / Medical Device studies, on request of the MHRA the Chief Investigator will submit detailed records of all adverse events that have been reported. 4.3 IMP SUSARs a. This section applies only where Papworth R&D is the sponsor or cosponsor of the research study using an IMP in which the SAE has occurred and where the investigator and / or sponsor has assessed the SAE to be a SUSAR. b. The R&D Department as the Sponsor s representative will report all SUSARs to: The Medicines and Healthcare Regulatory Agency (MHRA) The competent authorities (equivalent of the MHRA) of any EEA State, other than the UK, in which the trial is being conducted The REC that granted approval c. Papworth R&D will report within seven days of becoming aware of the event where these are fatal or life threatening and within fifteen days where the SUSAR was not assessed as life threatening or fatal. d. The R&D Department will report any additional relevant information to the bodies described above within eight days of the last report. e. Initial notifications of SUSARs may be made by fax, e-mail or telephone. Follow-up reports and all other safety reports should be sent to the REC office by post. f. Each submission of a SUSAR Sponsor report form to the main REC must be accompanied by the NRES Safety Report form for CTIMPs available at mailto:http://www.hra.nhs.uk/resources/during-and-after-your-study/progress-andsafety-reporting/ g. A single form may be used for the submission of several safety reports relating to the same trial. Reports should not normally cover more than one trial. However, the REC may permit this where two trials are very closely connected such as a main study and an extension study with the same treatment regime. 4.4 Non-IMP SUSARs a. Where Papworth R&D is the sponsor or cosponsor of a blinded non-imp study, the R&D department will report all SAEs that are assessed as non-imp SUSARs by either the investigator or the unblinded assessor to the research ethics committee that granted approval within 15 days using the NRES Report of Serious Adverse Event form available Version 3.2 Review Date: April 2016 Page 10 of 16

at: mailto:http://www.hra.nhs.uk/resources/during-and-after-your-study/progress-andsafety-reporting/ b. Follow-up of pregnancy within CTIMPs c. Pregnancy does not meet the definition of an SAE, but a congenital abnormality or birth defect is classed as an SAE. d. For all CTIMPs, if a pregnancy occurs either in a female subject or the female partner of a male subject the pregnancy should be followed up until at least the end of the pregnancy. e. The investigator is responsible for notifying the sponsor as soon as they become aware of a pregnancy. f. The Investigator must obtain informed consent for follow-up of the pregnancy from the trial subject (or their partner in the case of male subjects). g. Following the end of the pregnancy an SAE form must be completed if there is a congenital abnormality or birth defect. 4.5 Annual Safety, Annual Progress and End of Study Reports a. Where Papworth R&D is the sponsor or cosponsor, at the request of the Chief Investigator, the R&D department will assist the Chief Investigator in compiling the Annual Safety, Annual Progress and End of Study Reports. See SOP062 Preparation of Development Safety Update Reports. b. In meeting such requests the R&D Department will take all reasonable efforts to ensure that no information that could unblind and therefore compromise the study is provided directly to the Chief Investigator, unless the Chief Investigator is already unblinded. 5 Risk Management / Liability / Monitoring & Audit a. The R&D SOP Committee will ensure that this SOP and any future changes to this document are adequately disseminated. b. The R&D Department will monitor adherence to this SOP via the routine audit and monitoring of individual clinical trials and the Trust s auditors will monitor this SOP as part of their audit of Research Governance. From time to time, the SOP may also be inspected by external regulatory agencies (e.g. Care Quality Commission, Medicines and Healthcare Regulatory Agency). c. In exceptional circumstances it might be necessary to deviate from this SOP for which written approval of the Senior R&D Manager should be gained before any action is taken. SOP deviations should be recorded including details of alternative procedures followed and filed in the Investigator and Sponsor Master File. Version 3.2 Review Date: April 2016 Page 11 of 16

d. The Research and Development Directorate is responsible for the ratification of this procedure. Version 3.2 Review Date: April 2016 Page 12 of 16

Appendix 1: Assessment of Adverse Events Intensity The assessment of intensity will be based on the investigator s clinical judgement using the following definitions: Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities Severe: An event that prevents normal everyday activities Causality The relationship between the drug / device / procedure and the occurrence of each adverse event will be assessed and categorised as below. The investigator will use clinical judgement to determine the relationship. Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors etc., will be considered. The Investigator will also consult the Investigators Brochure or other product information. Not related: Temporal relationship of the onset of the event, relative to administration of the product, is not reasonable or another cause can by itself explain the occurrence of the event. Unlikely: Temporal relationship of the onset of the event, relative to administration of the product, is likely to have another cause that can by itself explain the occurrence of the event. Possibly related: Temporal relationship of the onset of the event, relative to administration of the product, is reasonable and the event could have been due to another, equally likely cause. Probably related: Temporal relationship of the onset of the event, relative to administration of the product, is reasonable and the event is more likely explained by the product than any other cause. Definitely related: Temporal relationship of the onset of the event, relative to administration of the product, is reasonable and there is no other cause to explain the event, or a re-challenge (if feasible) is positive. Where an event is assessed as possibly related, probably related, definitely related the event is an adverse reaction. Version 3.2 Review Date: April 2016 Page 13 of 16

Diagram depicting how Causality determines what is an event and what is a reaction. Expectedness Adverse reactions must be considered as unexpected if they add significant information on the specificity or severity of an expected adverse reaction. The expectedness of an adverse reaction shall be determined according to the reference documents as defined in the study protocol (e.g. investigator brochure or marketing information). For Papworth Sponsored studies all expected events must be listed in the protocol. Expected: Reaction previously identified and described in the protocol or reference documents e.g. Investigator Brochure (IB) or Summary of Product Characteristics (SmPC). Unexpected: Reaction not previously described in the protocol or reference documents. NB the protocol must identify the reference documentation used. Seriousness An event is considered serious if it meets one or more of the following criteria: Results in death Is life-threatening Requires hospitalisation or prolongation of existing hospitalisation Results in persistent or significant disability or incapacity Consists of a congenital anomaly or birth defect Further Document Information Version 3.2 Review Date: April 2016 Page 14 of 16

Approved by: Management/Clinical Directorate Group Approval date: (this version) Ratified by Board of Directors/ Committee of the Board of Directors: Date: Research and Development Directorate 13 th June 2013 (Chairman s action) STET N/A Medicines for Human Use (Clinical Trials) Regulations 2004 and all associated amendments. Research Governance Framework for Health and Social Care (2005) This document supports: Standards and legislation Key related documents: EN ISO 14155: 2011 Clinical Investigations of medical devices for human subjects Good Clinical Practice ISO/TS 19218-1:2011 Medical Devices Hierarchical coding structure for adverse events Part 1: Event type codes EN ISO 14971: 2007 Medical Devices Application of risk management to medical devices Trust Research Policy Research and Development Standard Operating Procedures entitled: SOP019 Research Protocol SOP037 Substantial Protocol Amendment SOP062 Preparation of Development Safety Update Reports. Trust s policy for the reporting of accidents / adverse events / incidents and defects (DN70) Equality Impact Assessment: Does this document impact on any of the following groups? If YES, state positive or negative, complete Equality Impact Assessment Form available in Disability Equality Scheme document DN192 and attach. Groups Disability Race Gender Age Sexual orientation Religious & belief Other Yes/No No No No No No No No Positive/Negative Review date: April 2016 Version Control Version 3.2 Review Date: April 2016 Page 15 of 16

Version Date effective Valid to Approved by Date of approval 1.0 July 2011 RDD 5 th August 2009 2.0 10 th February 2012 February 2014 RDD 10 th February 2012 3.0 22 nd August 2013 April 2016 RDD (chairman s action) 13 th June 2013 3.1 12 th February 2015 April 2016 HRA link updated 3.2 12 th May 2015 April 2016 Formatting updated 4.0 Version 3.2 Review Date: April 2016 Page 16 of 16