STANDARD OPERATING PROCEDURE

Transcription

1 STANDARD OPERATING PROCEDURE Title Reference Number Non Compliance and Serious Breach Reporting SOP-RES-017 Version Number 2 Issue Date 29 th Sep 2016 Effective Date 10 th Nov 2016 Review Date 10 th Nov 2018 Author(s) Reviewer(s) Teresa O Leary, Head of Regulatory Compliance Melanie Boulter, QA Auditor Authorisation (Original signatures are retained by Research & Innovation) Dr Stephen Ryder Director of Research & Innovation Dr Stephen Fowlie Medical Director 01 st Aug nd Sep 2016 USERS OF THIS STANDARD OPERATING PROCEDURE MUST REFER TO TO ENSURE THE MOST CURRENT VERSION IS BEING USED

2 Page 2 of Document History Version Issue Date Reason for Change Number 1 7 th May 2014 Original SOP. It replaces SOP th Sep 2016 Biennial review

3 Page 3 of Introduction The inherent risk in carrying out research, particularly in Clinical Trials of Investigative Medicinal Products (CTIMPs), means appropriate practices must be followed by research teams which are in turn monitored by the sponsor and regulatory authorities, such as the Medicines and Healthcare products Regulatory Agency (MHRA). Failure to comply with the study protocol, study-specific or sponsor procedures or policies, or non-compliance with the application regulations and legislative requirements for the study (such as The Medicines for Human Use (Clinical Trials) Regulations 2004, Good Clinical Practice (ICH-GCP), Research Governance Framework or The Medical Devices Regulations 2002 and ISO Clinical Investigation of Medical Devices for Human Subjects) must be documented and reported to the study sponsor. The study sponsor must ensure that any serious breaches are reported to the appropriate bodies within the appropriate timeframe. The Medicines for Human Use (Clinical Trials) Regulations 2004 as amended, contains a requirement that the sponsor of a clinical trial shall notify the licensing authority in writing of any serious breach of the conditions and principles of Good Clinical Practice (GCP) in connection with that trial; or the protocol relating to that trial, within 7 days of becoming aware of that breach. 3. Purpose and Scope The purpose of this standard operating procedure (SOP) is to describe the process for handling non-compliances and potential serious breaches for studies sponsored by Nottingham University Hospitals NHS Trust (NUH). Contractual arrangements between NUH and the Chief Investigator (CI) make it clear that the CI is required to notify the relevant NUH staff of any incident which they judge may have the potential to be regarded as a serious breach. This SOP also applies to deviations relating to NUH sponsorship processes (including quality systems) and form part of internal systems deviations. For studies not sponsored by NUH, the research team must ensure they comply with the study sponsor requirements for non-compliance and serious breach reporting. 4. Responsibilities Research Team or External Service Provider Any individual undertaking delegated activities for a research study must report any noncompliance to the sponsor.

4 Page 4 of 10 Sponsor (fulfilled by the Research and Innovation (R&I) department on behalf of NUH) The Research Project Manager (RPM) will review all non-compliances for the study as well as deviations from sponsor processes. The RPM will escalate any issues or serious breaches to the) Head of Regulatory Compliance (HRC) or delegate who will initiate appropriate corrective and preventative actions (CAPA) for the non-compliance and report any serious breach to the Competent Authority (CA) and/or Research Ethics Committee (REC). The RPM will be responsible for implementing urgent safety measures if necessary. The Head of Regulatory Compliance (HRC) is responsible for ensuring internal systems deviations are raised for non-compliance with the internal Quality Management System (QMS) and/or sponsorship GCP processes. All internal systems deviations are tracked and reported by HRC.

5 Page 5 of Definitions CA CAPA CI CTIMPs GCP HRC ICH-GCP IMP ISF MHRA NHSP NUH QMC R&I REC RPM Serious Breach TMF UK Competent Authority (in the United Kingdom this is the MHRA) Corrective and Preventative Action Chief Investigator Clinical Trials of Investigative Medicinal Products Good Clinical Practice Head of Regulatory Compliance International Conference on Harmonisation for Good Clinical Practice Investigational Medicinal Product Investigator Site File Medicines and Healthcare products Regulatory Agency Nottingham Health Science Partners Nottingham University Hospitals NHS Trust Queens Medical Centre Research and Innovation Research Ethics Committee Research Project Manager A serious breach is likely to effect to a significant degree the safety or physical or mental integrity of the participants of the study; or the scientific value of the study Trial Master File United Kingdom 6. Procedure All non-compliance with the study protocol, study-specific or sponsor procedures or policies, or non-compliance with the application regulations and legislative requirements for the study must be documented and retained in the Trial Master File (TMF) and/or Investigator Site File (ISF). Deviations from study protocols and procedures can occur in studies from time-to-time. The majority of these instances are technical deviations that do not result in harm to the study participants or significantly affect the scientific value of the reported results of the study. These deviations do not need to be reported to the CA and/or REC. Any serious breach of: i. the conditions and principles of GCP in connection with that study; or ii. the protocol relating to that study, as amended from time to time

6 Page 6 of 10 must be reported to the CA and/or REC. A serious breach is a breach which is likely to effect to a significant degree: i. the safety or physical or mental integrity of the study participants (this should be relevant to participants in the UK); or ii. the scientific value of the study. Protocol deviations to inclusion/exclusion criteria are NOT permitted may be considered a serious breach. The final study report or publication should list all significant non-compliances. 6.1 Identifying a Non-Compliance A non-compliance may be identified by any member of the research team, any member of staff of an external service provider undertaking delegated aspects of the research or the sponsor (during monitoring, for example). Examples of non-compliance are provided in Appendix 1. Upon identification of the non-compliance the organisation committing the deviation must complete a Deviation Report form (TAFR01701) and submit it to the sponsor immediately after becoming aware of the non-compliance. Deviation Report forms must be submitted by any of the following methods: i. (ResearchSponsor@nuh.nhs.uk); ii. Fax ( ); or iii. Hand delivered (R&I, NHSP, C Floor, South Block, QMC) If it is not possible to submit the Deviation Report form in a timely manner the sponsor should be contacted by telephone ( ) immediately. If some information about the non-compliance is not available at the time of notifying the sponsor this must be provided as soon as possible, but not later than 3 days from the initial notification. The person/organisation submitting the Deviation Report form must respond to the sponsor should a request for further information be made. Research sites should maintain a list of non-compliances at their site using the Deviation Log (TAFR01702). Deviation Report forms and the Deviation Log must be retained in the ISF. 6.2 Processing and Handling a Non-Compliance

7 Page 7 of 10 On receipt of the Deviation Report form, if the RPM deems it is missing information, the details of the non-compliance are unclear or the CAPA is inadequate they will contact the person who submitted the Deviation Report form for clarification. Once the RPM is satisfied they have all the information about the non-compliance and the CAPA was appropriate the RPM will sign-off the Deviation Report form, record it in the Deviation Tracker (TAFR01703) and retain a copy in the TMF. The RPM must escalate any non-compliance issues (e.g. recurring patterns) or potential serious breaches to the HRC immediately. If the HRC determines a serious breach has occurred section 6.3 must be followed. It may be that an isolated non-compliance is not considered serious, however repeated non-compliance of the same nature or on a wider-scale may be considered serious. The HRC will assess what CAPA may need to be implemented as a result of the noncompliance, including if it is a serious breach (e.g. a monitoring visit, an audit, site staff retraining, implementation of an urgent safety measure or protocol amendment). CAPA will be managed in accordance SOP-QMS-008 Corrective and Preventative Actions. CAPA will be fully documented in the TMF. It may be necessary to inform the organisation manager, site PI and/or the study CI about the non-compliance and CAPA. In this instance, the HRC/RPM will make the appropriate contact and retain this documentation in the TMF. 6.3 Reporting a Serious Breach If the non-compliance is deemed as serious by R&I the HRC will complete and submit a serious breach notification to the relevant Competent Authority (CA) and/or REC within 7 days of being made aware of it. Details of the breach should be circulated to any relevant members of NUH. For CTIMPs, the MHRA Notification of Serious Breach of Good Clinical Practice or Trial Protocol form available from the MHRA website will be used. For all other studies the Serious Breach Notification form (TAFR01704) will be used. If there is indisputable evidence that a serious breach has occurred the HRC will take action simultaneously with notifying the CA and/or REC. It is acceptable for the HRC to submit follow up information to the CA/REC, as long as the initial notification is made within 7 days of becoming aware of the serious breach. The CA may request additional information such as a copy of the protocol, independent ethics committee documentation, etc. The QAM will collate such documents and forward them to the CA. After notification follow up actions may include: i. Investigation of suspected fraud or misconduct (refer to SOP-RES-018 Fraud and Misconduct).

8 Page 8 of 10 ii. If the nature of the incident is such that urgent safety measures are necessary the RPM should ensure that they are implemented without delay (refer to SOP-RES-022 Urgent Safety Measures) iii. Organising changes to the audit programme. The serious breach must be documented in the TMF. 7. Internal Systems Deviations Deviations or instances of non-compliance where R&I personnel have not complied with sponsorship processes (including quality systems) must be tracked as part of the internal systems deviation. For study specific, the non-compliance can be raised using the study Deviation Report form (TAFR01701). A copy should be filed within the TMF and as part of the Internal Deviation folder (held with HRC) and added to the internal systems deviation log: Located:\R&D\QA\QA Internal Deviations For quality systems and general sponsor processes, non-compliances can be raised using the Internal Systems Deviation Report (TAFQ00804). This form is filed within the Internal Deviation folder (held with HRC) and added to the internal systems deviation log: Located:\R&D\QA\QA Internal Deviations A copy should also be filed within the specific study TMF. Internal Systems deviations are reported quarterly as part of QA metrics to senior management and to the Deputy Director of R&I. 8. References and Associated Documents Research Governance Framework for Health and Social Care: Second Edition, 2005 The Medicines for Human Use (Clinical Trials) Regulations 2004 and subsequent amendments International Conference on Harmonisation Guidelines for Good Clinical Practice E6 (R1) The Medical Devices Regulations 2002 and subsequent amendments ISO Clinical Investigation of Medical Devices for Human Subjects SOP-QMS-008 SOP-RES-018 SOP-RES-022 TAFR01701 TAFR01702 TAFR01703 TAFR01704 Corrective and Preventative Actions Fraud and Misconduct Urgent Safety Measures Deviation Report Deviation Log Deviation Tracker Serious Breach Notification

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10 Page 10 of 10 Appendix 1. Examples of Non-Compliance This list is not exhaustive: Recruiting a participant that does not meet the study protocol inclusion/exclusion criteria A missed visit window due to a participant not turning up for an appointment A blood sample not taken at the appropriate time-point (i.e. at +2 hours rather than at +1 hour) Incorrect assessment performed at a specific time-point An assessment was not completed at a specific time-point IMP temperature excursion Dosing error Failure to report a serious adverse event within the appropriate time-frame Implementing an amendment without the appropriate approval or authorisation being in place Early destruction of study files