STANDARD OPERATING PROCEDURE FOR RESEARCH. 2. Notification of Serious Breaches of Good Clinical Practice or Study Protocol

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1 Basildon and Thurrock University Hospitals NHS FT Research & Development APPROVED STANDARD OPERATING PROCEDURE FOR RESEARCH 2. Notification of Serious Breaches of Good Clinical Practice or Study Protocol 1. BACKGROUND This Standard Operating Procedure (SOP) describes procedures for identifying and reporting serious breaches of Good Clinical Practice (GCP) or study protocol. The EU GCP Directive 2005/28/EC was transposed into UK law as the Medicines for Human Use (Clinical Trials) Amendment Regulations 2006, together with the Medicines for Human Use (Clinical Trials) Regulations Under the amendment it is now a requirement that serious breaches of GCP or the study protocol are reported to the Medicines and Healthcare products Regulatory Agency (MHRA) (if appropriate), Research Ethics Committee (REC) in addition to the sponsor and Basildon and Thurrock University Hospitals NHS Foundation Trust (BTUH) research and development (R&D) department. The amended regulations state: 29A. (1) The sponsor of a clinical trial shall notify the licensing authority in writing of any serious breach of (a) The conditions and principles of GCP in connection with that trial; or (b) The protocol relating to that trial, as amended from time to time in accordance with regulations 22 to 25, within 7 days of becoming aware of that breach. (2) For the purposes of this regulation, a serious breach is a breach which is likely to effect to a significant degree (a) The safety or physical or mental integrity of the subjects of the trial; or (b) The scientific value of the trial It is the responsibility of the study sponsor or a person legally authorised by the sponsor to carry out the notification procedure within 7 days of becoming aware of the breach. Examples of serious breaches are show below and in Appendix 1; Failure to obtain informed consent (i.e. no documentation in source data or an Informed Consent Form) Enrolment of subjects that do not meet the inclusion/exclusion criteria Undertaking a study procedure not approved by the REC and/or the Medicines and Healthcare products Regulatory Authority (MHRA) (unless for immediate safety reasons) Page 1 of 5

2 Failure to report a serious adverse event (SAE), serious adverse reaction (SAR) or suspected unexpected SAR (SUSAR ) to the sponsor Investigational medicinal product (IMP) dispensing/dosing error Deviations from research study protocols and GCP occur commonly in research studies. The majority of these instances are technical deviations that do not result in harm to the research participant or significantly affect the scientific value of the reported results of the study. These cases should be documented e.g. in the case report form (CRF) for the study, in order for appropriate corrective and preventative actions to be taken. In addition, these deviations should be included and considered when the study report is produced (if BTUH sponsored), as they may have an impact on the analysis of the data. However, not every deviation from the protocol needs to be reported to the REC/MHRA as a serious breach. The reporting procedures for protocol violation/deviation are usually defined in the research study protocol. It is the responsibility of the to assess the impact of the breach on the scientific value of the study. Anyone who is unsure whether a breach has occurred can contact the R&D department to discuss the situation and clarify whether a breach is classed as serious. 2. PURPOSE The purpose of this SOP is to; outline procedures for identifying a potential serious breach of GCP or protocol violation describe the process for notification of serious breaches of GCP or the approved study protocol ensure appropriate assessments are carried out by relevant parties and fully documented outline the role of the R&D department in assessing the reported serious breaches and the escalation process 3. APPLICABLE TO This SOP applies to all staff involved in research studies sponsored or hosted by BTUH. For research studies sponsored by BTUH, notification of serious breaches should be directed to the study CI or delegated individual within 24 hours of being aware of the serious breach. For research studies hosted by BTUH, notification of serious breaches should be directed to the study sponsor within the specified timescales. The Associate Director of R&D should also be informed if a serious breach has occurred within BTUH whether BTUH sponsored or hosted. 4. PROCEDURE It is the responsibility of the CI and Principal Investigator(s) (PIs) to continually monitor the conduct of the research study; this may be delegated to a suitably qualified or experienced member of the research team or sub-contracted to an appropriately qualified party (e.g. coordinating centre). 4.1 BTUH ed Studies Procedure Identifying and Notification of a Serious Breach Page 2 of 5

3 If a possible protocol violation and/or GCP breach has been identified, the CI should carry out an assessment to confirm if the event affects the safety, physical or mental integrity of the research participant or the scientific value of the study. If yes, this should be treated as a possible serious breach and should be investigated further. However, if the event only relates to a protocol violation, then record the event as per protocol requirements. Any potential serious breaches of GCP identified either through monitoring, audit or by other means must be reported to the Associate Director of R&D within 24 hours of the breach being identified. For BTUH sponsored multicentre research studies, the process for identifying breaches should be provided to all participating sites at study set up. BTUH/sponsor should also ensure that adequate procedures are in place as part of the routine monitoring processes to identify potential GCP breaches. If a possible breach has been reported by a PI at a participating site or identified as part of the routine monitoring process, this SOP should be followed to conduct the necessary assessment and reporting required by the sponsor Assessment of a Serious Breach Upon notification of an initial breach report, R&D will discuss the issue with the CI or delegated individual to identify which section of GCP or the protocol has been breached and how the breach impacts the participants safety and/or the scientific integrity of the study. R&D will meet with the site study team to discuss the breach and compile evidence to support notification to the appropriate bodies. This will then be sent to the CI and related departments e.g. pharmacy, for approval. R&D will work with the study team to identify the extent of the breach and to initiate any urgent safety measures that may be required Initial Notification of Breach to external bodies CI/BTUH/sponsor will collate all available information and the PI and R&D will assist as required, the breach would then be reported to REC and MHRA (as appropriate) on the necessary forms, see Health Research Authority (HRA) and MHRA websites for most current forms Outcome The outcome of any serious breach along with corrective measures will be discussed with the PI and research team. Depending on the severity and frequency of the serious breach the site team may require additional training and monitoring and, as a last resort, the site may be suspended to further recruitment. 4.2 BTUH Hosted Studies Procedure Identifying and Notifying of a Serious Breach If a possible breach has been reported by a PI at a participating site or identified by the as part of the routine monitoring process, this SOP should be followed to conduct the necessary assessment and reporting required by the sponsor. Page 3 of 5

4 If BTUH R&D identifies the serious breach via our internal audit system the PI should notify the CI/sponsor within 24 hours of BTUH R&D becoming aware of the event Assessment and Outcome of a Serious Breach The PI and research team will provide the CI/sponsor with all necessary information to assist with the assessment of a serious breach in GCP. Any actions identified by the CI/sponsor should be implemented as soon as practical Other Reporting Requirements and Implementing Corrective and Preventative Action Any possible serious breach that occurs may also require reporting via BTUHs incident reporting system. The R&D Office shall make recommendations to the study team about where further reporting requirements apply. The R&D Office will work with the study team to devise a formal plan of corrective and preventative action to address the breach. Depending on the initial assessment of seriousness and impact, R&D may carry out a full audit of the study and general study management systems and procedures. 5. SUPPORTING DOCUMENTS Research Management and Governance Manual (CP/PO/00136) 6. REFERENCES SI 2004/1031: The Medicines for Human Use (Clinical Trials) Regulations 2004 SI 2006/1928: The Medicines for Human Use (Clinical Trials) Amendment Regulations APPENDICES Appendix 1: MHRA Serious Breach Examples 8. DOCUMENT HISTORY Revision Date Previous Revision Date Summary of Changes July 2014 New SOP Removing information regarding BTUH as sponsor requiring Competent Authority (MHRA) approval Changes Marked Whole document Page 4 of 5

5 APPENDIX 1: MHRA Serious Breach Example Notifier Breach Is it considered a Serious Breach? Dosing error. Ethics Committee & MHRA No. As no significant impact on the integrity of trial informed. Subjects withdrawn. The sponsor subjects or on scientific validity of the trial. stated that there were no serious consequences to subjects or data. Patient Information Leaflet and Informed Possibly not. If this was not a systematic or persistent Consent updated. At one trial site this was not problem and if no harm to trial subjects resulted from relayed to the patients until approximately 2-3 the delay. months after approval. More information on the potential consequences of the delay Yes, if there was a significant impact on the integrity should have been provided. of trial subjects (e.g. there was key safety information not relayed to subjects in a timely manner etc.). Visit date deviation. A common deviation in clinical trials. No. Minor protocol deviation, which does not meet the criteria for notification. Contractor Identified during an Inspection Investigator failed to report a single SAE as No, if it did not result in this or other trial subjects defined in the protocol (re-training provided). being put at risk, and if it was not a systematic or persistent problem. In some circumstances, failure to report a SUSAR could have a significant impact on trial subjects. Sufficient information and context should be provided for the impact to be assessed adequately. Investigator site failed to reduce or stop trial Yes medication, in response to certain laboratory parameters, as required by the protocol. This occurred with several patients over a one year period, despite identification by the monitor of the first two occasions. Patients were put at increased risk of thrombosis. Became aware of fraud at an investigator site Although, in this situation, not a legal requirement in the UK, which did not affect the overall under 29A, MHRA encourages voluntary reporting of scientific value of the s trial or the all fraud cases in the UK, because MHRA will need to integrity of trial subjects in the UK. However, establish the impact on the other trials in case subject the is aware that the investigator site integrity or the scientific value of those trials was was also involved in trials being sponsored by compromised. other organisations. IMP temperature excursions reported No, if the excursions had been managed appropriately (i.e. IMP moved to Alternative location/quarantined as necessary and it was identified by qualified personnel that there was no impact on stability of the product and therefore no impact on patient safety/data integrity). Yes, if this went unmanaged and subjects were dosed with the IMP were found to have become unstable and this resulted in harm or potential harm to subjects Page 5 of 5