STANDARD OPERATING PROCEDURE Title Reference Number Urgent Safety Measures SOP-RES-022 Version Number 1 Issue Date 30 th April 2014 Effective Date 28 th May 2014 Review Date 28 th May 2016 Author(s) Reviewer(s) Stacey Harrison, QA/GCP Manager Maria Koufali, Deputy Director of Research & Innovation Authorisation (Original signatures are retained by Research & Innovation) Dr Brian Thomson Director of Research & Innovation Dr Stephen Fowlie Medical Director 25 th April 2014 28 th April 2014 USERS OF THIS STANDARD OPERATING PROCEDURE MUST REFER TO WWW.NUHRISE.ORG TO ENSURE THE MOST CURRENT VERSION IS BEING USED
Page 2 of 7 1. Document History Version Issue Date Reason for Change Number 1 30 th April 2014 Original SOP.
Page 3 of 7 2. Introduction The health and safety of research participants must be protected at all times. The sponsor or investigator may take appropriate urgent safety measures (USMs) in order to protect research participants against any immediate hazard to their health or safety. These measures may include a deviation from- or change to- the protocol without obtaining prior approval from the Research Ethics Committee (REC), Competent Authority (CA) (for clinical trials of investigational medicinal products (CTIMPs). 3. Purpose and Scope This standard operating procedure (SOP) defines the process for implementing and reporting USMs taken by a researcher or the sponsor for any study sponsored by Nottingham University Hospitals NHS Trust (NUH). 4. Responsibilities Principal Investigator (PI) and Site Research Staff The PI, or other researcher, may implement USMs at their site at any time during the conduct of the study, but must report any actions taken to the Chief Investigator (CI) and sponsor immediately. Chief Investigator (CI) The CI may implement USMs for the study at any individual site, or across all sites (for multi-centre research), at any time during the conduct of the study, but must notify the sponsor immediately. The Sponsor (fulfilled by the Research and Innovation (R&I) department on behalf of NUH) The Research Project Manager (RPM) will ensure that the CA (for CTIMPs) and REC is notified when an USM is implemented for a study. The sponsor may delegate this responsibility to a third party. The sponsor will also ensure that deviation reports are completed and submitted by the appropriate person in connection with the USM.
Page 4 of 7 5. Definitions AE CA CI CTIMP DMC Funder ICH-GCP ISF MHRA NHSP NUH PI PIS PV QMC R&I REC RPM SAE SOP TMF TSC USM Adverse Event Competent Authority (in the United Kingdom this is the MHRA) Chief Investigator Clinical Trial of an Investigational Medicinal Product Data Monitoring Committee Organisation or institution financing the research International Conference on Harmonisation Guidelines for Good Clinical Practice Investigator Site File Medicines and Healthcare products Regulatory Agency Nottingham Health Science Partners Nottingham University Hospitals NHS Trust Principal Investigator Participant Information Sheet Pharmacovigilance Queen s Medical Centre Research and Innovation Research Ethics Committee Research Project Manager Serious Adverse Event Standard Operating Procedure Trial Master File Trial Steering Committee Urgent Safety Measure; any action taken which deviates from approved study procedures in order to protect a research participant(s) from an immediate hazard to their health and safety 6. Procedure If, at any time during the conduct of a study, the PI (or other researcher), CI or sponsor identifies that there is a hazard to participant health and safety at either an individual site or across all sites (in multi-centre research) then immediate action must be taken to protect those participants. Hazards may be identified through day-to-day conduct of the study, through sponsor monitoring and pharmacovigilance (PV) activities (i.e. reviewing reported adverse event (AE)
Page 5 of 7 and serious adverse event (SAE) data), or other safety monitoring by Data Monitoring Committees (DMCs) and Trial Steering Committees (TSCs). Examples which may result in immediate hazards include: i. a serious breach of the protocol, procedures or Good Clinical Practice (GCP); ii. a series of adverse reactions or a single case of an unexpected serious adverse reaction or an increase in the intensity or frequency of expected events and reactions; iii. accident or incident; iv. serious omissions in the approved protocol. Urgent safety measures might include: i. a temporary halt to the study at one site or study-wide; ii. a change to study procedures; iii. the addition of new unapproved study procedures. 6.1 Implementing an Urgent Safety Measure If the PI, or other researcher, deems that immediate action needs to be taken to protect the health and safety of study participants they must not delay in implementing the action. The PI, or other researcher, must notify the CI and sponsor (and PI if not already aware) immediately providing information about what actions were taken and why. The sponsor may be contacted by any of the following methods: i. Email (ResearchSponsor@nuh.nhs.uk) ii. Fax (0115 8493295) iii. In person (R&I, Nottingham Health Science Partners (NHSP), C Floor, South Block, Queens Medical Centre (QMC)) iv. Telephone (0115 9709049) Confirmation of receipt of the USM must be returned to the sender by the CI and sponsor in writing (by email). The sponsor will discuss the USM with the CI to determine if the hazards affect one site only or if participants at other sites are at risk, in which case the CI will instruct other sites to implement the USM immediately by contacting each PI, or another appropriate researcher at the site should the PI be unavailable. The DMC or TSC, or sponsor or CI, may deem that a USM must be implemented following review of study data. If this should occur, either at one site, or across all sites, the CI will contact the PI/s, or other appropriate researcher/s, immediately providing instructions of what actions must be taken and why.
Page 6 of 7 The sponsor will discuss with the CI the appropriate action to be taken following the implementation of the USM (i.e. amendment to protocol or participant information sheet (PIS)). The CI will be responsible for ensuring actions are addressed. 6.2 Reporting an Urgent Safety Measure The sponsor should discuss the USM with the Medicines and Healthcare products Regulatory Agency (MHRA) (for CTIMPs only) and REC immediately by telephone. This may be delegated to the CI. In any case, the sponsor must notify the MHRA (for CTIMPs only) and the REC in writing of the USM within 3 working days by submitting a covering letter clearly identifying the submission as an urgent safety measure (setting out the reasons and the plan for further action), a substantial amendment notification form and any supporting documents, such as a revised protocol. In the case of a CTIMP being conducted during a disease pandemic period the USM may be submitted to the MHRA as soon as possible (i.e. not necessarily within 3 working days). If appropriate for the study, the CI must also inform the chairs of the DMC and TSC, and the Funder, if they are not already aware of the USM. 6.3 Re-consent for Study Participants All study participants affected by the USM must be notified of it as soon as possible by the PI. Participants must be given the option to re-consent to take part in the study, or withdraw, following the implementation of a USM. The sponsor and CI must agree how information will be provided to participants, and how consent will be taken. It is acceptable for unapproved information sheets and consent forms to be utilised in this situation, but they should be submitted to the CA (for CTIMPs) and REC with the notification (see 6.2). Notification of the USM to participant, re-consent, or withdrawal, must be documented within the participants medical notes by the site. 6.4 Documenting the Urgent Safety Measure The R&I RPM will ensure the USM is appropriately documented in the investigator site file (ISF) and trial master file (TMF); that is copies of all correspondence, amended study
Page 7 of 7 documents, amendment submissions and approvals and any subsequent researcher training in relation to the USM will be filed in the TMF. It may be appropriate to complete a Deviation Report Form (TAFR01701), in which case the RPM will facilitate this in accordance with SOP-RES-017 Non-Compliance and Serious Breach Reporting. 6.5 Withdrawal of Sponsorship or Premature Discontinuation of the Study The sponsor should perform a risk assessment as a result of the USM, ideally before notifying the MHRA (for CTIMPs) and REC, but this must not delay the reporting of the USM (refer to SOP-RES-002 Risk Assessment). Sponsorship may be withdrawn if the USM means that NUH is no longer able to fulfil its obligations as sponsor (i.e. it does not have the capacity, resources or finance to oversee the changes to the study as a result of the USM). In this circumstance refer to SOP-RES-001 Sponsorship. The CI and/or sponsor may decide that the hazards to participant health and safety are so significant that the study is not safe to continue despite implementation of a USM. In this circumstance refer to SOP-RES-025 End of Study Notification and Premature Discontinuation of a Study. 7. References and Associated Documents The Medicines for Human Use (Clinical Trials) Regulations 2004 and subsequent amendments International Conference on Harmonisation Guidelines for Good Clinical Practice E6 (R1) Good Clinical Practice Guide compiled by the Medicines and Healthcare products Regulatory Agency, published 2012 TAFR01701 SOP-RES-001 SOP-RES-002 SOP-RES-017 SOP-RES-025 Deviation Report Form Sponsorship Risk Assessment Non-Compliance and Serious Breach Reporting End of Study Notification and Premature Discontinuation of a Study