STANDARD OPERATING PROCEDURE SOP 205

Transcription

1 STANDARD OPERATING PROCEDURE SOP 205 Adverse Events: Identifying, Recording and Reporting for CTIMPs Sponsored by the Norfolk and Norwich University Hospital NHS Foundation Trust Version 2.3 Version date 14 th December 2016 Effective date 1 st April 2017 Number of pages 21 Review date December 2018 Author NNUH UEA Joint Research Office Approved by Melissa Cambell-Kelly Role Research Matron Signature Date Authorised by Role Professor Alastair Forbes Chief of Research and Innovation Signature Date 1/4/17 COPIES PRINTED FROM THE WEBSITE ARE VALID ONLY ON THE DAY OF PRINTING SOP 205 v2.3 Effective Date: Page 1 of 21

2 It is the responsibility of all users of this SOP to ensure that the correct version is being used. All staff should regularly check the NNUH R&D website for information relating to the implementation of new or revised versions of SOPs. Staff must ensure that they are adequately trained in the new procedure and must make sure that all copies of superseded versions are promptly withdrawn from use. The definitive versions of all Joint NNUH/UEA health care research SOPs appear online. If you are reading this in printed form please check that the version number and effective date is the most recent one as shown on the NNUH R&D website. Acknowledgements: This protocol has been adapted with permission of Imperial College Clinical Research Governance Office. TABLE OF CONTENTS 1 ABBREVIATIONS 3 2 INTRODUCTION 3 3 SCOPE 5 4 DEFINITIONS 5 5 RESPONSIBILITY 9 6 PROCEDURE Assessment of all AE s Reference/ comparator Drugs SAE reporting SUSAR reporting Unbinding Timeframe for expedited reporting esusar reporting Multi-Centre studies CI and Trial management group procedure for Multi-Centre 16 studies 6.6 Urgent Safety Measures Trust Reportable incidents For studies being carried out by NNUH Pregnancy Reporting for NNUH Sponsored Studies 17 7 REFERENCES 18 8 RELATED DOCUMENTS 19 9 LIST OF APPENDICES 19 Appendix 1 Flow chart for Reporting SAEs 20 Appendix 2 Change Control, Revision and Review Sheet 21 SOP 205 v2.3 Effective Date: Page 2 of 21

3 1 ABBREVIATIONS AE AR CI CRF DSUR DMC GCP IB IDMC ICH IMP NIMP NNUH MAH MHRA PI REC R&D SAE/SAR SOP SmPC SSAR SUSAR TMG TSC UAR UEA USAR Adverse Event Adverse Reaction Chief Investigator Case Record Form Developmental Safety Update Report Data Monitoring Committee Good Clinical Practice Investigator Brochure Independent Data Monitoring Committee International Conference for Harmonisation Investigational Medicinal Product Non-Investigational Medicinal Project Norfolk and Norwich University Hospitals NHS Foundation Trust Marketing Authorisation Holder Medicines and Healthcare products Regulatory Agency Principal Investigator Research Ethics Committee Research & Development Serious Adverse Event/Reaction Standard Operating Procedure Summary of Product Characteristics Suspected Serious Adverse Reaction Suspected Unexpected Serious Adverse Reaction Trial Management Group. Trial Steering Committee. Unexpected Adverse Reaction University of East Anglia Unexpected Serious Adverse Reaction 2 INTRODUCTION This SOP is for all staff members at the NNUH and the UEA who are involved in healthcare research and has been produced in accordance with the Medicines for Human Use (Clinical Trials) Regulations 2004 to ensure that systems are in place for pharmacovigilance, and the recording, managing and reporting of adverse events in Clinical Trials of Investigational Medicinal Products (CTIMPs). It describes the process for recording, managing and reporting Adverse Events in CTIMPs that are sponsored by the NNUH. At present (April 2017) CTIMPs are not sponsored by UEA, but if this position changes, the same criteria and processes will apply. SOP 205 v2.3 Effective Date: Page 3 of 21

4 In order to comply with the Medicines for Human Use (Clinical Trials) Regulations 2004, and Standards for Good Clinical Practice (GCP), it is important that all researchers are aware of the different definitions related to adverse events in research and how to record, report and review each of these specific occurrences. It is essential that all adverse events which occur during the course of a study are recorded and reported appropriately in order to ensure that patient safety is maintained. Adverse events are reportable from the time of participant study enrolment unless study specific exclusions are detailed in the clinical trial protocol. The Chief Investigator (CI) /Principal Investigator (PI) must be aware of the Trust and UEA systems for reporting adverse events and should read and agree to adhere to this SOP to comply with the conditions of approval for studies sponsored in accordance with the Joint Research Governance Policy between NNUH and UEA. Adverse events affecting Trust research participants must continue to be reported into the Trust s clinical risk systems and other regulatory frameworks as stated in this SOP. All CTIMPs must have a sponsor legally responsible for the conduct and monitoring of the trial. The NNUH Research & Development Office will be responsible for ensuring monitoring is conducted for all CTIMPs for which the Trust acts as Sponsor, unless there is an explicit arrangement to the contrary. In order to ensure the continuing safety of study participants it is essential that all adverse events which occur during the course of a participant s involvement in a clinical research study are appropriately recorded and reported. The Medicines for Human Use (Clinical Trials) Regulations 2004 and the Department of Health s Research Governance Framework for Health and Social Care, or its successors, set out specific requirements for the managing of adverse events (AE). Of particular importance is the assessment of any event for causality and expectedness. Consequently, AEs can be classified into different categories (further explanations are given in section 4) 1. Adverse Event (AE) 2. Adverse Reaction (AR) 3. Serious Adverse Event / Serious Adverse Reaction (SAE/SAR) 4. Suspected Serious Adverse Reaction (SSAR) 5. Suspected Unexpected Serious Adverse Reaction (SUSAR) Each type of AE is subject to different reporting requirements. It is important that this SOP is followed, as failure to report incidents, or deal with incidents adequately, can result in regulatory approval being withdrawn from an individual project, or, in more extreme cases, from all research conducted by an SOP 205 v2.3 Effective Date: Page 4 of 21

5 individual investigator, and with adverse consequences to the Sponsor and the host institution. 3 SCOPE This SOP applies to all Clinical Trials of an Investigational Medicinal Product sponsored by NNUH. The principles within this document must be followed. However, if applicable, and only with prior agreement with the sponsor, the content may be modified to be study specific and meet the needs of individual studies. It is the responsibility of the local PI to ensure that study specific SOPs can be operated without conflict with this SOP and in accordance with all organisational polices related to research. 4 DEFINITIONS The following definitions are taken from the Medicines for Human Use (Clinical Trials) Regulations The definition of an adverse event given below is that used in the clinical trials regulations. However, for the avoidance of doubt, when following the SOP all AE/SAE/SUSARs should be recorded for all trial subjects from the time of their enrolment into the study, whether an IMP has been administered to the subject or not. Unless study specific exclusions are detailed in the clinical trial protocol, the time of enrolment is defined as the point at which the decision is made and documented by the investigator, or delegated individual, that the subject is eligible to participate in the study and that consent has been received. Investigational Medicinal Product (IMP) An investigational Medicinal Product (IMP) is a pharmaceutical form of an active substance or placebo being tested or used as a reference/comparator in a clinical trial. This includes a medicinal product which has a marketing authorisation but is, for the purposes of the trial, being used or assembled, formulated or packaged; a) In a way different from the approved form or b) Being used for an unapproved indication or c) When used to gain further information about an approved use. Non-Investigational Medicinal Product (NIMP) Products that are not the object of investigation (i.e. other than the tested product, placebo or active comparator) may be supplied to subjects participating in the trial and used in accordance with the protocol. SOP 205 v2.3 Effective Date: Page 5 of 21

6 These might be, for example, medicinal products such as support/rescue medications for preventative, diagnostic or therapeutic reasons and/or to ensure that adequate medical care is provided for the subject. These medicinal products do not fall within the definition of investigational medicinal products (IMPs) in Directive 2001/20/EC and are called non-investigational medicinal products (NIMPs). Adverse Event (AE) An adverse event is defined as any untoward medical occurrence in a study participant who has been administered a medicinal product, as IMP or comparator; the event does not necessarily have a causal relationship with this treatment. Comment: An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an IMP, whether or not considered related to the IMP. NB: Not all adverse events are adverse reactions but all adverse reactions are adverse events. Intensity: The intensity of an adverse event will initially be assessed according to the following definitions: Intensity Mild Description An event easily tolerated by the patient, causing minimal discomfort and not interfering with everyday activities. Moderate An event sufficiently discomforting to interfere with normal everyday activities Severe An event that prevents normal everyday activities Adverse Reaction (AR) Adverse reactions are defined to include all untoward and unintended responses to an IMP related to any dose administered. Comment: All adverse events judged by either the reporting investigator or the sponsor as having a reasonable causal relationship to the IMP qualify as adverse reactions. SOP 205 v2.3 Effective Date: Page 6 of 21

7 Causality The relationship between IMP and the occurrence of an 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 need to consider the expectedness of the event. Relationship Not related: Unlikely: *Possibly related: *Probably related: *Definitely related: Description Temporal relationship of the onset of the event, relative to administration of the product, is not reasonable or another cause can itself explain the occurrence of the event. Temporal relationship of the onset of the event, relative to administration of the product, is doubtfully related, or the event could have been due to another, equally likely cause. Temporal relationship of the onset of the event, relative to administration of the product, is reasonable but the event could have been due to another equally likely cause. 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. 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 or definitely related, the event is an adverse reaction. Expectedness: The expectedness of an adverse reaction shall be determined according to the reference documents as defined in the study protocol. The protocol must identify the reference documentation used i.e. the Summary of Product Characteristics (SmPC)/ Investigator Brochure (IB). Expected Reaction previously identified and described in the protocol and/or reference documents e.g. IB/ SmPC SOP 205 v2.3 Effective Date: Page 7 of 21

8 Unexpected Reaction not previously described in the protocol or reference documents. Unexpected Adverse Reaction (UAR) An unexpected adverse reaction is an adverse reaction, the nature and severity of which is not consistent with the information about the medicinal product in question set out in the: a) Summary of product characteristics (Smpc or SPC) - in the case of a product with a marketing authorisation. b) Investigator s brochure - in the case of any other investigational medicinal product relating to the trial in question. When the outcome of the adverse reaction is not consistent with the applicable product information, this adverse reaction should be considered as unexpected. Serious Adverse Event / Reaction (SAE/SAR) An adverse event or adverse reaction is defined as serious if it: a). Results in death or b). Is life-threatening* or c). Requires hospitalisation or prolongation of existing hospitalisation or d). Results in persistent or significant disability or incapacity or e) Consists of congenital anomaly or birth defect or f). Other: e.g. Is otherwise considered medically significant by the investigator. *Comment: Life-threatening, in the definition of an SAE or SAR, refers to an event in which the subject was at risk of death at the time of event; it does not refer to an event which hypothetically might have caused death if it were more severe. Medical judgement should be exercised in deciding whether an adverse event/reaction is serious in other situations. Important adverse events/reactions that are not immediately life-threatening or do not result in death or hospitalisation but may SOP 205 v2.3 Effective Date: Page 8 of 21

9 jeopardise the subject or may require intervention to prevent one of the other outcomes listed in the definition above, should also be considered serious. A planned hospitalisation for a pre-existing condition, or a procedure required by the trial protocol, without a serious deterioration in health, is not considered to be a serious adverse event unless specified in the clinical trial protocol. Suspected Serious Adverse Reaction (SSAR) Any adverse reaction that is classed as serious and is consistent with information listed in either the: a) Summary of product characteristics (SmPC or SPC) - in the case of a product with a marketing authorisation. b) Investigator s brochure - in the case of any other investigational medicinal product relating to the trial in question. The SmPC or IB should be reviewed regularly to ensure that the most up-to-date version is in use, and a protocol review should be undertaken if required. The site file should be annotated to show that this check has been undertaken. Suspected Unexpected Serious Adverse Reaction (SUSAR) A SUSAR is a suspected unexpected serious adverse reaction in that it is unexpected according to the: c) Summary of product characteristics (SmPC or SPC) - in the case of a product with a marketing authorisation. d) Investigator s brochure - in the case of any other investigational medicinal product relating to the trial in question. The trial protocol should include a list of known side effects for each IMP in the study. This should be checked with each event that occurs in terms of expectedness. If the event is not listed as expected, or has occurred in a more serious form than anticipated, this should be considered a SUSAR. A serious adverse event that is unexpected and thought to be related to an investigational medicinal product is only considered to be a SUSAR after the treatment code is broken and active treatment is confirmed. That is, the SAE can only become a SAR following confirmation of active treatment. The reaction only becomes a USAR if the SAR is unexpected. Adverse Incident An adverse incident can be defined as an event or circumstance that could have or did lead to unintended or unexpected harm, loss or damage. SOP 205 v2.3 Effective Date: Page 9 of 21

10 5 RESPONSIBILITY There are a number of responsibilities when managing adverse events. Below is a list of responsibilities for the investigator and NNUH R&D. 5.1 Investigator responsibilities The Chief Investigator (CI) has overall responsibility for the conduct of the study. The Principal Investigator (PI) has responsibility for the research at a local site where the study involves specified procedures requiring site-specific assessment. There should be one PI for each research site. In the case of a single-site study, the CI and the PI may be the same person. The Investigator must ensure that the dignity, rights, safety and well-being of the subjects 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 time-frame. 5.2 R&D responsibilities for NNUH Sponsored Studies The sponsor 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. The Sponsor is responsible for expeditious reporting to the regulatory authority unless responsibility is formally delegated. As soon as a trial for which NNUH is Sponsor receives Notification of Acceptance from the MHRA, the research services manager, or a delegated individual, will ensure that the trial is appropriately registered on the local portfolio management system. The research services manager, or a delegated individual, will register the trial on the MHRA electronic reporting site for SUSARs ( The generated esusar account will be identifiable by trial title, CI and Eudract number. Prior to commencing study recruitment, investigators and study personnel will receive training relating to their responsibilities for adverse event reporting for NNUH sponsored studies as part of the site initiation visit. Independent Data Monitoring Committee: It is recommended that an Independent Data Monitoring Committee (IDMC) is appointed in order to review safety data regularly throughout the trial, and, when necessary, to recommend to the Sponsor whether to continue, modify or terminate SOP 205 v2.3 Effective Date: Page 10 of 21

11 the trial. This procedure must be defined in the protocol. As with all recording and reporting, subject confidentiality and adherence to the Data Protection Act (1998) must be maintained on all reports. Development Safety Update Report (DSUR) Requirements: The sponsor is responsible for the preparation, content and submission of the Development Safety Update Report (DSUR) to the regulatory authority and Research Ethics Committee on an annual basis or upon request. This responsibility can be delegated by the Sponsor to the CI. The Joint Research Governance Committee undertakes the Research Governance functions for healthcare research involving the NNUH and UEA, according to the Joint Research Governance Policy. A Clinical Trials Unit (CTU) may be formally delegated Sponsor responsibilities as recorded in the Delegation of Sponsor Responsibilities section within the clinical trial agreement. Where these responsibilities include Pharmacovigilance they will be carried out in line with the relevant CTU Working Practice documents. 6 PROCEDURES 6.1 Assessment of all Adverse Events Unless explicit in the protocol, for the avoidance of doubt, all AE/SAE/SAR/SSAR/SUSARs should be recorded for all trial subjects from the time of their enrolment into the study, whether an IMP has been administered to this subject or not. The time of enrolment is defined as the point at which the decision is made and documented by the PI, or delegated individual, that the subject is eligible to participate in the study following the receiving of consent. In the event of an adverse event/reaction, the investigator (or delegated member of the research team) must review all documentation (e.g. hospital notes, laboratory and diagnostic reports) relevant to the event. The event and relevant comments must then be recorded in the subject s medical notes (or source data where this is not the medical notes). For all adverse event/reactions the investigator (or delegated member of the research team) will make an assessment of intensity, causality, seriousness and relationship to the IMP. Detailed guidance on making this assessment is given in section 4. Except where the protocol states otherwise, all adverse event/reactions that are not considered serious should be recorded in detail on a case record form (CRF) or SOP 205 v2.3 Effective Date: Page 11 of 21

12 equivalent to allow analysis at a later stage. The completed form should be filed along with the other CRFs for the study and a copy provided to the Sponsor as agreed. 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. At the conclusion of the study all adverse event/reactions, occurring during a study must be subject to statistical analysis and that analysis and subsequent conclusions must be included in the final study report. If the administered product is a comparator the event will be assessed for expectedness as per the SmPC or IB, and if considered unexpected and related to the event then it will be subject to expedited reporting as a potential SUSAR. The flowchart in Appendix 1 is designed to enable Investigators/research personnel to assess AEs and SAEs should they occur during the trial and to decide if the event requires further expedited reporting. If an AE occurs that is likely to affect safety of the subjects the CI must take appropriate urgent safety measures to protect the patients against immediate hazard (see SOP 230). 6.2 Reference/Comparator drugs and study procedures Often more than one drug is used in a clinical trial in order to meet the objectives of the trial. When considering patient safety ALL drugs used are of interest. Non-investigational medicinal products (NIMPs) used in the trial may also be subject to reporting requirements and details should be provided in the study protocol. The following scenarios when an adverse reaction to a NIMP would require reporting: a) If the adverse reaction is suspected to be linked to an interaction between a NIMP and an IMP and is serious and unexpected. b) If a SUSAR is reported and it might be linked to either a NIMP or an IMP but cannot be attributed to only one of these. c) If an adverse reaction associated with the NIMP is likely to affect the safety of the trial subjects. SARs associated with a NIMP should be reported to the Marketing Authorisation Holder (MAH) in order that this information may be used in the MAH s ongoing safety monitoring procedures. SOP 205 v2.3 Effective Date: Page 12 of 21

13 A SAR associated with a NIMP which does not have a Marketing Authorisation in the UK must be notified to the licensing authority. In some circumstances trial subjects may experience an SAE which is not related to the study product but which is related to the research (such as study procedure). Such SAEs must be reported to the sponsor using the SAE report form. 6.3 Serious Adverse Event Reporting Within 24 hours of any member of the research team becoming aware of a serious adverse event the Sponsor must be notified as documented in the protocol. The only exception is where the protocol or Investigator s Brochure identifies the event as not requiring immediate reporting. Investigator: The investigator or delegated individual will complete the NNUH SAE Reporting form. The initial report will include as much information as is available at the time. The completed form must be sent to R&D within 24hrs of any member of the research team becoming aware of the event either by; to: rdsae@nnuh.nhs.uk or In person to the R&D office, NNUH The chief Investigator must be copied in to the notification. The investigator will provide any information missing from the initial report as soon as possible, within a maximum of 2 working days of the initial report being sent to R&D. R&D & Investigator: R&D will acknowledge receipt of the SAE notification by the noon of the following working day; either to the address from which the initial notification was received or contact number provided. If acknowledgement of the SAE is not received by the person sending the notification by the noon of the following working day, then it is the responsibility of the Investigator (or delegated member of the research team) to contact R&D immediately. Follow on Reporting SOP 205 v2.3 Effective Date: Page 13 of 21

14 Investigator: After submitting the initial report the investigator is required to actively follow up the subject until either: a) The SAE/SUSAR resolves, or b) The sponsor and CI/PI agree that no further follow-up required*. *This decision must be documented in the TMF. It will be the Chief Investigator s decision as to how long the SAE/SUSAR will be followed up. Investigators (or delegated persons) will provide follow-up information, each time new information is available. A follow up report should be submitted as soon as any new information becomes available. The NNUH SAE Report Form will be completed and submitted by either: to: rdsae@nnuh.nhs.uk or In person to the R&D office, NNUH The chief Investigator must be copied in to the notification. R&D: The research governance administrator, or delegated individual, will liaise with the investigator and/or trial manager to gain an update regarding the progress of the SAE/SUSAR and follow up reporting until either: a) The SAE/SUSAR resolves, or b) The Sponsor and CI/PI agree that no further follow up is required. 6.4 SUSAR Reporting Any AE that the PI evaluates as serious, is suspected of having a causal relationship to the IMP and is unexpected, will require expedited reporting to NNUH R&D Office, MHRA, REC and to other organisations as required under the terms of the individual contracts (eg relevant pharmaceutical companies, other NHS Trusts). If the CI, or Trial Management Group is not in agreement with the expectedness decision of the PI, the CI cannot overrule the PI s decision. Both opinions should be recorded on the SAE form. SUSARs should be reported following the timelines in section If the Clinical Trials Unit (CTU) is responsible for the management of a trial, NNUH may delegate the reporting responsibilities to the CTU trial manager. This decision will be documented in the protocol and clinical trial agreement. SOP 205 v2.3 Effective Date: Page 14 of 21

15 6.4.1 Unblinding Systems for SUSAR reporting should, as far as possible, maintain blinding of individual clinicians and of local trial staff involved in the day-to-day running of the trial. It is important that the details of the unblinding process are included in the trial protocol. For blinded trials involving a placebo and an active drug, seriousness, causality and expectedness should be evaluated as though the patient was on active drug. Cases that are considered serious, unexpected and possibly, probably or definitely related (i.e. possible SUSARs) would have to be unblinded. For blinded clinical trials, the blind must be broken by the Sponsor for all SUSARs before they are reported to the competent authority for that specific subject (even if the CI/PI remains blinded). This is in order to provide meaningful information that can enable evaluation of the data in the context of the safety profile of the IMP. If the Sponsor has delegated responsibility for pharmacovigilance management and reporting, then unblinding should be performed by individuals who are not involved in the everyday trial management (eg the IDMC or site pharmacist). Reference should also be made to other SOPs which include information on unblinding, e.g. SOP Timeframes for expedited reporting Fatal/life threatening SUSARs The CI must inform the NNUH R & D Office (sponsor) of fatal or life-threatening SUSARs as soon as possible. The Sponsor, or delegated individual, must inform the competent authority of fatal or life-threatening SUSARs as soon as possible, but no later than 7 calendar days after the CI has first knowledge of the minimum criteria for expedited reporting. The relevant follow-up information should be sought and a report completed as soon as possible. This should be sent within an additional 8 calendar days. The Sponsor, or delegated individual, must inform the REC, of fatal or lifethreatening SUSARs as soon as possible but no later than 7 calendar days after the CI has first knowledge of the minimum criteria for expedited reporting. Definition of Day 0 - Please note that the timelines for expedited reporting define day 0 as the day that the CI receives notification of the event. Non- fatal and non-life threatening SUSARs The CI must report all other SUSARs to the NNUH R&D Office (Sponsor). The Sponsor, or delegated individual, must inform the MHRA as soon as possible, but no later than 15 calendar days after the CI has first knowledge of the minimum criteria SOP 205 v2.3 Effective Date: Page 15 of 21

16 for expedited reporting. Further relevant information should be given as soon as possible. Definition of Day 0 - Please note that the timelines for expedited reporting define day 0 as the day that the CI receives notification of the event esusar Reporting: The NNUH R&D Office (sponsor), or delegated individual, is responsible for the reporting of SUSARs via the MHRA electronic reporting site for SUSARs ( If pharmacovigilance management and reporting has been delegated, the CI or trial manager must send a copy of the esusar report to the Sponsor. esusar automatically populates the trial details in the report by first selecting the trial for which the report is to be made. The form guides the user through a series of steps collecting information on the Trial Subject, the reaction and the IMP. The user s details are automatically populated into the report and are defined by their account. Prior to submission of the report, a summary of the data collected is presented and the user has the option to amend any details. The user also has the option to download a full report in either PDF format or as XML. These reports can be useful for informing Ethics Committees. As well as creating and submitting new reports, users can submit follow-up reports, edit previously created but as yet unsubmitted reports, and create and submit copy reports based on previous reports. NB: Once a report has been submitted it cannot be altered and any amendments will need to be included in follow-up reports. 6.5 Multi-centre studies Each AE must be evaluated according to the definitions for intensity, causality, seriousness, and expectedness (as detailed in section 4). The responsibility for this evaluation can be shared between the CI and PIs and this must be stated in the delegation of responsibilities between the Sponsor, CI, and PI. It may be most appropriate for the treating PI at each local site to evaluate each event, before reporting it to the CI. It must be stated in the clinical trial protocol who will take responsibility for the assessment and reporting of such events to the Sponsor and CI simultaneously. As expedited reporting may be required, this SOP assumes that responsibility of initial assessment and reporting to the CI lies with the PI Chief Investigator and Trial Management Group procedure for multicentre studies SOP 205 v2.3 Effective Date: Page 16 of 21

17 a) Completed SAE Forms from sites are re-assessed by the CI. The CI will decide if he/she agrees with the PI on the classification or whether the status of the event should be upgraded to SUSAR. The CI may not downgrade an event graded by a PI as a SUSAR. b) An entry of the details of the event must be made in the SAE log in the TMF. All logged events will be reported to the REC and competent authority annually in the DSUR. c) The study Trial Management Group must ensure that they regularly review SAEs, looking for possible trends, etc. The review sessions must be minuted as having taken place, with a note of the attendees, and the SAEs that have been reviewed. d) If an event is identified as a SUSAR, expedited reporting is required as detailed in Section 6.4 d) The CI, or delegated individual, will send a monthly study update report to the NNUH R&D office for review by the Joint Research Governance Committee. If there is nothing new to report, an must be sent to the NNUH R&D office to confirm this. Reporting SUSARs to PIs involved in a multi-centre Study For all multi-centre studies where NNUH is the sponsor, the research services manager, or delegated individual, must inform all Principal Investigators of SUSARs occurring on the study, although this does not have to be within the 7/15 day deadline. This notification must be documented in the TMF. The same will apply where other trials are being undertaken within the Trust of the same study drug. If the CI is informed of SUSARs from other trials by a pharmaceutical company, the CI, or delegated individual, should inform PIs as above. 6.6 Urgent Safety Measures Urgent Safety Measures are covered in SOP Trust Reportable Incidents In the same way that adverse incidents, including clinical, non-clinical and near misses can involve patients, staff and visitors during routine care, adverse incidents can also occur during research related activities. It is important that research related adverse incidents are treated in the same way as non-research related adverse incidents. Research related adverse incidents must therefore be reported in accordance with the Trust s own Incident Reporting procedures For studies being carried out within NNUH: SOP 205 v2.3 Effective Date: Page 17 of 21

18 The research matron and research services manager should be alerted to all NNUH trust reportable incidents relating to research. An example of a research related adverse incident may be lost drugs. This is not an AE but should be reported as an adverse incident. Events that are both Adverse Incidents and Adverse Events MUST be reported independently following both processes and procedures. 6.8 Pregnancy Reporting for NNUH Sponsored Studies Should a study participant become pregnant whilst undertaking a CTIMP, or aid in the conception of a child whilst they are participating in a CTIMP, the pregnancy and resulting child should be followed up for a period of no less than 18 months to verify whether a congenital anomaly or birth defect is present. This will be subject to guidance from the relevant pharmaceutical company. Investigator responsibility: Pregnancy occurring in a participant or a female partner of a male participant in a Clinical Trial of Investigational Medicinal Product (CTIMP), while not considered an adverse event or serious adverse event must, be reported to the sponsor and CI within 7 days of the investigator becoming aware of the event. The PI/CI must collect all information required regarding the pregnancy. Guidance on the procedure for recording and reporting pregnancy should be included in the study protocol. Any occurrence that results in a SAE/SUSAR should also be reported as detailed in section 6.3 and 6.4. R&D responsibility: The research services manager, or delegated individual, is responsible for reporting the event to the Marketing Authorisation Holder, or for nonlicensed products to the licensing authority, within 15 days of receiving the report. 7. REFERENCES a) Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use: b) Detailed guidance on the European database of Suspected Unexpected Serious Adverse Reactions (Eudravigilance Clinical Trial Module) c) The Medicines for Human Use (Clinical Trials) Regulations 2004 Part 5 d) National Research Ethics Service guidance on safety reporting: SOP 205 v2.3 Effective Date: Page 18 of 21

19 e) MRC/DH joint project, Work stream 6: Pharmacovigilance data/assets/pdf_file/0010/35956/joint-project-pharmacovigilance.pdf f) MHRA Clinical trials for medicines: Safety reporting SUSARS and ASRs Clinical trials for medicines: Safety reporting - SUSARs and ASRs : MHRA g) The rules governing medicinal products in the European Union Volume 10 Guidance documents applying to clinical trials Questions and Answers specific to adverse reaction reporting in clinical trials. me%2010%20version%201.0.pdf h) The rules governing medicinal products in the European Union Volume 10 Clinical Trials Notice to Applicants Chapter V Additional Information Questions and Answers _27_en.pdf 8. RELATED DOCUMENTS SOP 230 Urgent Safety Matters SOP 835 Trial Data Management System: EMERGENCY UNBLINDING NNUH UEA Joint Research Governance Policy 9. LIST OF APPENDICES Appendix 1: NHIR SAE reporting decision tree Appendix 2: Change Control, Review and Revision Sheet SOP 205 v2.3 Effective Date: Page 19 of 21

20 Appendix 1: Flow Chart for Reporting SAEs SOP 205 v2.3 Effective Date: Page 20 of 21

21 Appendix 2: Change Control, Revision and Review Sheet Change Control, Revision and Review Sheet: SOP 205 Version No Change Date Reason for Change /10/2012 Addition of procedures in relation to Urgent Safety Measures, Pregnancy and Follow up and Further Reporting of SAES /01/2014 Removal of SAE reporting template (Appendix 1), minor changes to Scope (para 3) and Responsibilities (para 5). Combining SOP change control and revision sheets. Reviewer: Designation: Signature & Date: /12/2016 Updates to table of contents and abbreviations due to major changes within the document. Section 6.4.1, 6.4.2, 6.4.3, and added. Large changes to procedures section. Removal of responsibilities from the appendices and placed within the SOP. Addition of dedicated SAE box for NNUH. Reviewer: Lisa Chalkley Designation: Research Services Manager Signature & Date: Review confirmation sent by . Saved in the S:\Corporate Departments\Research & Development\Shared\Research Governance\SOPs - DO NOT TOUCH\SOP Reviews \SOP 205 & 206 Reviewer: Designation: Signature & Date: SOP 205 v2.3 Effective Date: Page 21 of 21