Standard Operating Procedure

Standard Operating Procedure SOP number: SOP full title: SOP-JRO-07-004 Recording, managing and reporting Adverse Events for Clinical Trials of Investigational Medicinal Products and trials of Advanced Therapy Medicinal Products SOP effective: 13 Oct 2017 Review date: 13 OCT 2019 SOP author signature: SIGNED COPY HELD WITHIN THE JRO Rebecca Johnson, Research Governance Specialist SOP approval signature: SIGNED COPY HELD WITHIN THE JRO Ms Susan Ridge, Research Governance Manager SOP HISTORY Version Date Reason for change 001 10 July 2013 Changed in response to findings from MHRA GCP Inspection 002 31 July 2013 Changed to include ATMP trials and simplification of causality definitions 003 23 July 2015 Biannual Review. Minor administrative changes. 1. BACKGROUND/INTRODUCTION Patient safety should always be paramount during research. All adverse events that occur during the course of a study must be appropriately recorded and reported, in accordance with the protocol, in order to ensure the ongoing safety of study participants. The Medicines for Human Use (Clinical Trials) Regulations 2004 and the Research Governance Framework for Health and Social Care (Second edition 2005) set out specific requirements for the reporting of adverse events. Of particular importance is the assessment of causality and expectedness of the event. As such, adverse events can be classified depending upon these two factors (further information in section 4.1.). SOP Template Version 1.1, 12-2-12 Page 1 of 9 SOP-JRO-07-004

2. PURPOSE This Standard Operating Procedure (SOP) describes the process for recording, evaluating, notifying and reporting adverse events for Clinical Trials of Investigational Medicinal Products (CTIMPs) and trials involving Advanced Therapy Medicinal Products (ATMPs) where the trial is sponsored or hosted by The Newcastle upon Tyne Hospitals NHS Foundation Trust (NUTH FT). It is vitally important that this SOP is adhered to as failure to do so could result in regulatory approval being withdrawn from an individual project or, in extreme cases, from all research performed by a specific Chief Investigator (CI) or Principal Investigator (PI). 3. SCOPE This SOP is applicable to all staff involved in the conduct of CTIMPs or trials of ATMPS at NUTH FT. This SOP is also applicable to those members of the NUTH FT Research & Development (R&D) team within the Newcastle Joint Research Office (NJRO) with responsibility for reviewing adverse events, particularly those in the Regulatory Compliance Team. 4. PROCEDURE 4.1. Terminology The following definitions have been adapted from the Medicines for Human Use (Clinical Trials) Regulations 2004: Term Adverse Event (AE) Adverse Reaction (AR) Definition Any untoward medical occurrence in a patient or clinical trial participant administered an investigational product, which does not necessarily have a causal relationship with the study treatment. AEs can include abnormal laboratory findings, unfavourable symptoms or diseases. Any untoward and unintended response in the recipient of an investigational product which is related to any dose administered to that subject. All AEs determined to have a reasonable causal relationship to the investigational product qualify as ARs. SOP Template Version 1.1, 12-2-12 Page 2 of 9 SOP-JRO-07-004

Serious Adverse Event (SAE), Serious Adverse Reaction (SAR) or Unexpected Serious Adverse Reaction Suspected Unexpected Serious Adverse Reaction (SUSAR) Severity Any AE, AR or Unexpected Serious Adverse Reaction that results in: death a life-threatening event (i.e. that places the participant at immediate risk of death as the event occurred rather than an event that may have been life threatening had it been more severe) hospitalisation or prolongation of an existing hospitalisation a persistent or significant disability or incapacity a congenital anomaly or birth defect An important medical event may also be classified as serious if it jeopardises the participant or requires an intervention to prevent one of the above consequences. Any AR that is classified as serious and is suspected to be caused by the investigational product that is not consistent with the known safety information listed in the Investigator Brochure (IB) or Summary of Product Characteristics (SmPC). The term severe is used to describe the intensity of a specific event (e.g. mild, moderate or severe). The severity of an event is not the same as the seriousness; an AE can be severe but not serious. 4.2. Adverse Event Assessment 4.2.1. Causality Causality must be determined by a medically qualified clinician and this responsibility reflected in the site delegation log. The responsibility for assessing causality is delegated to the local PI for the relevant site, or the CI for single site studies. When determining the causality of an AE the investigator should take into account: the participant s medical history any lack of efficacy or worsening of condition under study the study treatment any concomitant medications that the participant is taking the relevant information provided in the protocol SOP Template Version 1.1, 12-2-12 Page 3 of 9 SOP-JRO-07-004

The AE should be assessed as to whether there is or is not a suspected causal relationship to the investigational product. A suspected causal relationship should be reported if there is: clear evidence to suggest a causal relationship and other contributing factors can be dismissed evidence to suggest a causal relationship and the influence of other factors is unlikely some evidence to suggest a causal relationship, however the influence of other factors may have contributed to the event incomplete or insufficient evidence to make a clinical judgement of the causal relationship If there is little or no evidence to suggest a causal relationship between the event and the investigational product or if there is another reasonable explanation for the event, a causal relationship should not be assigned. 4.2.2. Expectedness The responsibility for determining expectedness is also delegated from NUTH FT to the local PI for the relevant site, or CI if the trial is single site. The expectedness must be assessed solely against the reference safety information as listed in the protocol. The reference safety information is either contained in an IB or SmPC. 4.2.3. Seriousness The seriousness of an event must also be determined by a medically qualified clinician and this responsibility reflected in the site delegation log. The responsibility for assessing seriousness is delegated to the local PI for the relevant site, or the CI for single site studies. Seriousness must be assessed against the standard definition (section 4.1.). 4.3. Study Planning The clinical trial protocol should refer to the known side effects and ARs as listed in the IB or SmPC. The AE reporting and recording requirements should also be detailed in the protocol and be in proportion to the risks of the trial. A record of all AEs must be kept in the Trial Master File (TMF). 4.3.1. Which AEs to Record? It is the Sponsor s responsibility to determine which AEs require recording and reporting. The initial risk assessment conducted for the trial should be used to inform the requirements, e.g. for high risk trials all AEs must be recorded, however for low risk trials the decision may be made to record only SAEs or events of particular concern. SOP Template Version 1.1, 12-2-12 Page 4 of 9 SOP-JRO-07-004

4.3.2. Which SAEs to Report? The management and reporting arrangements for SAEs must be in place for all CTIMPs and trials of ATMPs. Agreements at the beginning of the trial should be made for such SAEs that can be defined as disease-related and therefore not subject to expedited reporting. It is recommended that an independent Data Monitoring Committee (DMC) is appointed in order to review safety data regularly throughout the trial and when necessary recommend to the Sponsor whether to continue, modify or terminate the trial. This procedure must be defined in the protocol. 4.4. Event Recording and Reporting during the Trial 4.4.1. AEs All AEs must be recorded in the participant s medical notes and the following documented each time: description of the event event duration - start and stop dates and times (if appropriate) suspected or known cause severity and whether the event is classified as serious details of any action taken in response to the event treatments given to or taken by the participant including nondrug therapies results of any assessments conducted in relation to the event (e.g. ECG findings, full blood count, etc) investigator assessment of relationship of event to the investigational product If required by the protocol, the AE should also be recorded on the appropriate Case Report Form (CRF). The participant should be followed up by the research team until the event abates and as per protocol, with relevant information documented in the medical notes. 4.4.2. SAEs If an AE is assessed as serious, the PI (or medically qualified clinician on the site delegation log who has been delegated responsibility for SAE reporting by the PI) must report the event to the CI or delegated Clinical Trials Unit (CTU)/Sponsor s pharmacovigilance representative immediately or within 24 hours of being made aware of the event. (The exception to this are those SAEs identified in the protocol as not requiring immediate reporting.) SOP Template Version 1.1, 12-2-12 Page 5 of 9 SOP-JRO-07-004

The initial report can be made verbally but must be promptly followed with a detailed, written report. The PI or delegate must record the event with their assessment of seriousness (along with causality, expectedness and severity) on a trial SAE form. The PI should ensure that follow-up information is provided when available. The CI must include all SSARs and SUSARs in the Development Safety Update Report (DSUR) (see 4.5.). SAEs occurring in NUTH FT sponsored studies must be notified to NUTH FT R&D in accordance with the agreed risk assessment. For those trials managed by the CI, a copy of the SAE form must be submitted directly to Sponsor via email to tnu-tr.safetyreporting@nhs.net. For those trials managed by a CTU, NUTH FT R&D and the CTU will determine the best method for notification (e.g. use of the Soho66 Fax to Email service). The frequency of the submission will be determined by the individual requirements of the trial. All reports for SAEs occurring in NUTH FT sponsored studies will be reviewed by an appropriately qualified member of the Regulatory Compliance Team /NUTH FT R&D Department to check that all essential information has been completed (including causality), whether or not the event may be classed as a SUSAR, that the report has been signed off appropriately and that it has been submitted in a timely manner. Any queries should be addressed to the CI or CTU, as appropriate. As Sponsor s representative, NUTH FT R&D will put systems in place to ensure that all SAEs are tracked appropriately and that SAEs are reported correctly within the regulatory timelines and followed up until conclusion. 4.4.3 SUSARs Any AE that meets the definition of a SUSAR will require expedited reporting to the Medicines and Healthcare products Regulatory Agency (MHRA) and Research Ethics Committee (REC) (see SOP-JRO-03: Sponsor processes for reporting Suspected Unexpected Serious Adverse Reactions ). For NUTH FT sponsored studies this is the responsibility of the NUTH FT R&D team as Sponsor representatives. All CIs are responsible for providing the necessary information in order to report the SUSAR completely and within the regulatory timelines (this responsibility may be delegated to a CTU if appropriate). All SUSARs occurring in NUTH FT sponsored studies (whether experienced by patients from NUTH FT or another Trust hosting the study) must also be reported via the NUTH FT DATIX system. The incident type should be entered as Research Incident/Accident ; Directorate as Medical Director s Directorate ; Speciality as Research Development and Governance ; Site as Regent Point ; and Location as Research Buildings (entries selected from the drop down menus). Reporting via DATIX is the responsibility of an appropriately qualified member of the NUTH FT R&D team. (See also NUTH FT Managing and Reporting of Accidents and Incidents Policy). SOP Template Version 1.1, 12-2-12 Page 6 of 9 SOP-JRO-07-004

All SUSARs experienced by NUTH FT patients in NUTH FT hosted studies must be reported via email to the NUTH FT R&D Safety Reporting Inbox (tnu-tr.safetyreporting@nhs.net) by the PI or a member of the study team (in addition to reporting to the CI/Sponsor as directed by the study protocol). The SUSAR will then be reported via DATIX by NUTH FT R&D as above. 4.4.4. Pregnancy Should a study participant become pregnant or aid in the conception of a child, the pregnancy and resulting child should be followed up for the period specified within the protocol. The follow up period will be determined at the protocol development stage and will be informed by the known teratogenic potential of the product along with guidance from the Marketing Authorisation Holder (MAH). Informed consent must be obtained from the study participant and their partner before this can occur. 4.4.5. Investigational Product Overdose All cases of investigational product overdose, whether accidental or intentional, must be immediately relayed to NUTH FT R&D and CI, or delegated CTU if applicable. Details of the event must be recorded in the case report forms for the trial, the participant s medical notes and the AE log if appropriate. Any cases of overdose that meet the definition of a SAR must be subjected to expedited reporting accordingly. 4.5. Annual Reports Development Safety Update Report (DSUR) The Sponsor (or authorised delegate) must submit a safety report to the MHRA and REC once a year for the duration of the study. DSURs should be provided at yearly intervals from the date of the original exemption (for CTIMPs ongoing on 1 May 2004), or the date of the first Clinical Trial Authorisation approval (for CTIMPs starting after 1 May 2004). For those trials with marketed products, the DSUR is due the anniversary of the first marketing authorisation being granted in the European Union. The report should be comprehensive yet concise, including an evaluation of pertinent safety information collected during the reporting period related to the drug under investigation. Information must be provided to assure regulators that Sponsors (or their authorised delegate) are adequately monitoring and evaluating the evolving safety profile of the investigational product. Guidance on the required format, timing and submission procedures of safety reports is provided by the European Commission and the MHRA. SOP Template Version 1.1, 12-2-12 Page 7 of 9 SOP-JRO-07-004

The DSUR should also be submitted to NUTH FT R&D in a timely manner via the Regulatory Compliance Team s Safety Reporting Inbox: tnutr.safetyreporting@nhs.net. 5. REVIEW AND MONITORING OF THIS DOCUMENT This document will be reviewed every 2 years or if there is a change to the national guidance/regulations. The use of the SOP will be monitored during the annual audit cycle of research projects performed by NUTH FT R&D. 6. REFERENCES 6.1. The Medicines for Human Use (Clinical Trials) Regulations 2004 and amendments 6.2. The Research Governance Framework for Health and Social Care, Second Edition 2005 6.3. ICH Topic E2F Development Safety Update Report; http://www.ema.europa.eu/docs/en_gb/document_library/scientific_guideline/2009 /09/WC500002827.pdf 6.4. MHRA Guidance on Safety Reporting - https://www.gov.uk/clinical-trials-for-medicines-manage-your-authorisation-reportsafety-issues#l9 6.5. SOP JRO-03 Sponsor processes for reporting Suspected Unexpected Serious Adverse Reactions NJRO Website 6.6. Health Research Authority Annual Progress Reports: http://www.hra.nhs.uk/resources/during-and-after-your-study/nhs-rec-annualprogress-report-forms/ 6.7. NUTH FT - Managing and Reporting of Accidents and Incidents Policy 7. APPENDICES 7.1. AE Decision Tree SOP Template Version 1.1, 12-2-12 Page 8 of 9 SOP-JRO-07-004

7.1. AE Decision Tree Receipt of Adverse Event (AE) Assess Seriousness is AE serious? NO Record AE in medical notes. Record in CRF. YES Assess Causality - is the AE related to the IMP? NO Event is a SAE and must be reported within 24 hours of being aware of the event*. Event to be included in DSUR. YES NO Is the AE expected? Event is a SUSAR. Was the AE lifethreatening or fatal? YES Event is a SSAR. Inform the R&D Regulatory Compliance Team of the event via: tnu-tr.safetyreporting@nhs.net*. Report as an SAE. Event to be included in DSUR. YES NO SUSAR to be reported to Clinical Trials Unit & Sponsor within 24 hours of site awareness. Sponsor to report to MHRA/REC within 7 days of receipt. Event to be included in DSUR. SUSAR to be reported to Clinical Trials Unit & Sponsor within 24 hours of site awareness. SUSAR to be reported to MHRA/REC within 15 days of receipt. Event to be included in DSUR. * If a CTU is involved, event to be reported to the CTU in the first instance. SOP Template Version 1.1, 12-2-12 Page 9 of 9 SOP-JRO-07-004