Details: Author: Razwan Mahroof - QA Clinical Trials Monitor SOP Pages: 10 Version No. of replaced SOP: 1.0 Effective date of replaced SOP: 04 December 2015 Approval: Version No: of the SOP being approved. Name of person approving this SOP. Date Signature of the person approving this SOP. Clare Skinner Faculty Head of Research and Innovation Support Faculty of Medicine & Health University of Leeds Professor Steve Smye Director of Research & Innovation Leeds Teaching Hospitals NHS Trust Distribution & Storage: Distribution to Chief Investigators, Principal Investigators and to all members of staff working on CTIMPs sponsored by University of Leeds and Leeds Teaching Hospital Trust Location of Document Paper: Electronic: Quality Assurance, Research and Development, Leeds General Infirmary I:\QA\1_SPONSOR_LEEDS_DOCUMENTS\SOPs Page 1 of 10
CONTENTS 1. INTRODUCTION.3 2. APPLICABILITY...3 3. PHARMACOVIGILANCE ADVERSE EVENTS..3 SERIOUS ADVERSE EVENTS (SAEs)..4 Reporting SAEs to Sponsor QA office Completing the SAE form Submitting follow-up information SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR) 6 Reporting SUSARs Handling SUSARs from Blinded and Unblinded trials URGENT SAFETY MEASURES...7 Reporting Urgent Safety Measures to the MHRA Reporting to the Sponsor QA office ANNUAL SAFETY REPORTS / DSURs..9 Submitting reports to the MHRA Submitting reports to the REC 4. ACRONYMS..10 5. REFERENCES..10 Page 2 of 10
1. Section A Introduction 1.1 This SOP outlines the procedure for pharmacovigilance for LTHT and UoL sponsored Clinical Trials of Investigational Medicinal Products (CTIMPs). 1.2 Pharmacovigilance (PV) is defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. 1.3 For investigators this means monitoring the safety of the IMP and accurately recording and reporting any events to the Sponsor and regulatory authority in specified timelines. 1.4 This SOP will outline the steps required for: - Recording and reporting Adverse Events / Serious Adverse Events and Suspected Unexpected Adverse Events. - Implementation of Urgent Safety Measures. - Annual Safety Reporting / Development Safety Update Reports. 2. Section B Applicability 2.1 This SOP is applicable to all members of staff working on CTIMPs sponsored by Leeds Teaching Hospital Trust (LTHT) / University of Leeds (UoL). 2.2 Deviations from this SOP must be discussed and agreed with the Sponsor QA team during protocol development and a written agreement must be in place. 2.3 For CTIMPs managed by a Clinical Trials Research Unit (CTRU) a clear delegation of pharmacovigilance duties is required. The Sponsor must ensure these procedures are compliant with the clinical trial regulations. 3. Section C Pharmacovigilance 3.1 ADVERSE EVENTS (AEs) An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Page 3 of 10
3.1.1 Participants must be assessed for AEs at each trial visit (as per the trial protocol). An AE can be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporarily associated with the use of an Investigational medicinal product (IMP), whether or not related to the IMP. 3.1.2 All AEs must be recorded in the Case Report Form (CRF) and the patient s medical notes. 3.1.3 The investigator must assess adverse events for seriousness (as defined in the protocol) and causality; the decisions made should be fully documented and initialled in the medical notes and CRF. 3.1.4 Documentation of AEs and related source data will be checked during routine sponsor monitoring visits. (Please see LTU-QM23- A Researchers Guide to Source Documentation ) 3.2 SERIOUS ADVERSE EVENT (SAE) Any adverse event that results in death, is life-threatening, requires hospitalisation prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. 3.2.1 All adverse events meeting the seriousness criteria (as outlined above), and therefore assessed as an SAE by the CI/PI or medically qualified delegate must be reported to the Sponsor. 3.2.2 SAEs must be reported in line with the REC / MHRA approved protocol, which will include instructions regarding how long SAEs have to be captured and reported for e.g. XX days after last dose of IMP. 3.2.3 All SAEs must also be fully documented in the CRF and patient s medical notes 3.2.4 All SAEs must be assessed for causality. This assessment must be made by a medically qualified doctor who appears on the trial delegation log. 3.2.5 All adverse events judged by the investigator / medically qualified delegate as having a reasonable suspected causal relationship with the IMP qualify as Adverse Reactions Page 4 of 10
3.3 REPORTING SAES TO SPONSOR QA OFFICE 3.3.1 Upon identification of an SAE, the investigator or named delegate must report the SAE via email (leedsth-tr.sponsorqa@nhs.net) to the sponsor QA office within 24 hours of awareness (using the CTT21: SAE Report form). 3.3.2 Under no circumstances should reporting the SAE exceed 24 hours from time of awareness. 3.3.3 If the SAE is suspected to be related to the study treatment/s and is assessed to be unexpected, this qualifies as a Suspected Unexpected Serious Adverse Reaction (SUSAR) and additional action is required - please see section 3.6 for full details on SUSARs. 3.3.4 A scanned copy of the completed CTT21 SAE report form and include the following details in the subject field of the email : R&D number Trial short name SAE or SUSAR Notification 3.3.5 If initial attempts to obtain all necessary information needed to fully complete the SAE report have proved unsuccessful, the available information must still be provided to the sponsor within the timeframe specified above (3.3.1). 3.3.6 The research team are then required to provide follow up information to the Sponsor QA office as soon as possible to ensure a complete audit trail of each event. 3.3.7 If a full response has not been received from the QA office within 3 working days, please contact the QA team directly to discuss. 3.4 COMPLETING THE CTT21 SAE / SUSAR REPORT FORM 3.4.1 Only one SAE / SUSAR can be reported per form. 3.4.2 For SAE ID use the following: R&D number/patient ID/ SAE number - e.g. XXXX/0001/0003 represents trial number XXXX, patient number 1 with their third SAE. 3.4.3 The report form must be fully complete and legible as onward reporting may be required. The QA team will be in contact for further information if required 3.4.4 Where multiple options are listed, tick all that are applicable 3.4.5 Corrections must be initialled and dated. Page 5 of 10
3.4.6 Please use supplementary pages (CTT21A - SAE form Supplemental Page) to provide additional information if required 3.5 SUBMITTING FOLLOW UP INFORMATION 3.5.1 All SAEs must be followed up to resolution. 3.5.2 On a follow-up report, the completer of the form must highlight any changes and additional information before sending to the sponsor. 3.5.3 Notification of receipt will be provided by the QA office within 3 working days. If no response is provided within 3 working days please contact the QA team directly to discuss. 3.6 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR) A serious adverse reaction of which the nature and severity is not consistent with the applicable product information i.e. the information provided by the Summary of Product Characteristics (SmPC), Investigator Brochure (IB) 3.6.1 When an SAE is deemed unexpected when assessed against the Reference Safety Information (RSI) - the section of the IB or SmPC identified as such in the MHRA application and protocol - the SAE qualifies as a SUSAR and requires expedited reporting. 3.6.2 The expectedness assessment can be undertaken by the CI/PI or other medically qualified delegate. 3.6.3 In absence of both the CI and PI, a SUSAR must nevertheless be reported to the Sponsor and the regulator within the legislatively specified timelines 3.7 REPORTING SUSARS: 3.7.1 Upon identification of a SUSAR, the investigator or named delegate must report the SUSAR via email (leedsth-tr.sponsorqa@nhs.net) to the sponsor QA office immediately and within 24 hours of awareness (using the CTT21: SAE Report form). 3.7.2 The SUSAR box must be checked on the form to alert the QA team of the need for urgent review. Page 6 of 10
3.7.3 It is the investigators responsibility to provide the Sponsors QA team with follow-up information as soon as possible, to facilitate accurate onward reporting to the MHRA / REC 3.7.4 ALL SUSARs must be reported to the MHRA and REC in specified timelines. Unless otherwise agreed (See section B 2.2). The Sponsor QA team are responsible for reporting the SUSAR to the MHRA and REC in the timelines specified below. SUSARs that are fatal or life threatening must be reported to MHRA and REC within 7 days following date of awareness Further follow-up with any additional information relevant to the SUSAR must be reported within 8 days of submitting the initial report. SUSARs that are not fatal or life threatening must be reported to MHRA and REC no later than 15 days following date of awareness 3.8 HANDLING SUSARS FROM BLINDED TRIALS 3.8.1 SUSARs should be unblended prior to reporting to the REC and MHRA. Unbinding procedures can be found in your current REC / MHRA approved trial protocol (or formal written blinding procedure). 3.8.2 If the PI considers the event as an immediate hazard to the health and safety of the trial subject, an Urgent Safety Measure (USM) may be required. 3.9 URGENT SAFETY MEASURES An Urgent Safety Measure (USM) is an action that the Sponsor or Investigator may take in order to protect the subjects of a clinical trial against any immediate hazard to their health or safety. 3.9.1 The requirement for an Urgent Safety Measure may be primarily identified by the receipt of a Serious Adverse Event (SAE) or a Suspected Unexpected Serious Adverse Reaction (SUSAR), which then prompts the urgent implementation of a new protocol measure to prevent: A future occurrence of a safety issue or To prevent a recurrence of a safety issue 3.9.2 Examples of when an Urgent Safety Measure may be required are as follows: Serious adverse reactions with an unexpected outcome (e.g. death) An increase in the frequency of a serious adverse reaction which is judged to be clinically important Page 7 of 10
A serious adverse event associated with the study procedures which may be prevented by changing the procedures Lack of efficacy of an investigational medicinal product (IMP) used for the treatment of a life threatening illness A major safety issue identified from other studies (clinical or non-clinical) or from other usage of the IMP. 3.10 REPORTING URGENT SAFETY MEASURES TO THE MHRA 3.10.1 The MHRA must be notified immediately and, in any event within 3 days that such a measure has been taken and the reasons why it has been taken. 3.10.2 The Chief Investigator is responsible for notifying the MHRA, initially by telephone (MHRA s Clinical Trial Unit 020 3080 6456) within 24 hours. This will include a discussion with a safety scientist to outline the reasons for the Urgent Safety Measure. 3.10.3 The CI must then complete a written report which must be submitted to the MHRA within 3 calendar days of implementing the measure. 3.10.4 In parallel you must contact the Sponsor QA office - see section 3.11 3.11 REPORTING TO THE SPONSOR QA OFFICE: 3.11.1 The CI or delegate must inform the Sponsor QA office of the USM immediately by telephone. 3.11.2 A written report must then be submitted by completing. Section A of form CTT07-LTHT / UoL Notification of Urgent Safety Measure (and supplementary sheet CTT07B If applicable). This must be sent to the QA office via email (leedsth-tr.sponsorqa@nhs.net) within 24 hours of the measure being implemented. This report must be signed and dated 3.11.3 Upon receipt, the Sponsor QA office will review the information provided, according to the Sponsor s (LTU_QM_05_ LTHT UoL Sponsored CTIMP Urgent Safety Measures). The sponsor may seek advice from the joint University of Leeds and Leeds Teaching Hospitals NHS Trust data Monitoring Committee (DMC). 3.11.4 The Sponsor will respond within 3 calendar days, via e-mail that the form has been received and if any further information is required. 3.11.5 The Chief Investigator together with the Sponsor are responsible for reviewing the Urgent Safety measure and assessing the best way of implementing the relevant changes to the protocol / trial via a substantial amendment. Page 8 of 10
3.12 ANNUAL SAFETY REPORTING An annual safety report describing the general progress and any relevant safety data related to the trial that must be submitted to the main REC, MHRA and the Sponsor on the anniversary of the Clinical Trial Authorisation being granted. The annual report should follow the format of a Developmental Safety Update Report (DSUR) which should be a concise document and focus on the IMP. A template and guidance for the completion of this report is available from the Sponsor QA office. 3.12.1 The CI will receive an automated e-mail reminder from the Sponsor QA office to remind them that annual reports are due. The automated reminders are set up upon trial initiation. 3.12.2 A DSUR must then be completed by using the DSUR form (CTT55) and guidance document CTGN42. The final sign off must be that of the CI. 3.13 SUBMITTING REPORTS TO THE MHRA: 3.13.1 DSURs are to be submitted to the MHRA on the anniversary of the Clinical Trial Authorisation being granted by a member of the research team and a copy must be sent to the Sponsor QA office for their records. (CTRUmanaged trials are an exception to this as the CTRU has their own reminder and expediting process in place). 3.13.2 The DSUR report can be submitted to the MHRA via the following link http://cesp.hma.eu/home/index OR sent on a CD to the following address Information Processing Unit Area 6 Medicines & Healthcare Products Regulatory Agency 151 Buckingham Palace Road Victoria SW1W 9SZ For further guidance and updates on reporting to the MHRA, please use the following link https://www.gov.uk/guidance/clinical-trials-for-medicines-manage-your-authorisationreport-safety-issues#submit-development-safety-update-reports-dsurs Page 9 of 10
3.14 SUBMITTING REPORTS TO THE REC: 3.14.1 The DSUR should be submitted to the REC within 60 days of the reporting period. 3.14.2 The REC should receive the full DSUR including the line listings of SUSARs, however as per NRES guidance, the REC is only expected to review the executive summary. 3.14.3 An annual progress report also needs to be provided to the REC using the template form available on the HRA website: http://www.hra.nhs.uk/resources/during-and-after-your-study/nhs-researchethics-committee-rec-ctimp-safety-report-form/ 3.14.4 The REC Manager will acknowledge receipt of all safety reports within 30 days by signing and returning a copy of the covering form. Reports sent without the covering form will not be acknowledged. 4. ACRONYMS AE AR CI CTRU DMC DSUR HRA IMP MHRA mnca PI REC SAE SAR SUSAR Adverse Event Adverse Reaction Chief Investigator Clinical Trials Research Unit Data Monitoring Committee Development Safety Update Report Health Research Authority Investigational Medicinal Product Medicines and Healthcare products Regulatory Agency Model Non-Commercial Agreement Principal Investigator Research Ethics committee Serious Adverse Event Serious Adverse Reaction Suspected Unexpected Serious Adverse Reaction 5. REFERENCES MHRA Good Clinical Practice Guide http://www.hra.nhs.uk/ https://www.gov.uk/government/organisations/medicines-and-healthcare-productsregulatory-agency EC Directive (2001/20/EC) www.ct-toolkit.ac.uk Page 10 of 10