JOINT RESEARCH AND DEVELOPMENT OFFICE. Standard Operating Procedure for Investigators and the Joint R&D Office Staff SOP 22

Transcription

1 JOINT RESEARCH AND DEVELOPMENT OFFICE Standard Operating Procedure for Investigators and the Joint R&D Office Staff SOP 22 Updated By Praseeda Thaikalloor Clinical trials Manager Joint R&D office for GOSH/ICH Ext: (4) Author Biren Patel Clinical Trials Co-ordinator R&D Office for GOSH/ICH Approved by Emma Pendleton Deputy Director of Division of Research and Innovation R&D Office for GOSH/ICH Ext: (4) Page 1 of 13

2 (1) GOSH ICH GUIDES This document (also referred to as a Standard Operating Procedure: SOP) is identified by code GOSH ICH/11/S22/01. The code identifies the origin of the document (GOSH ICH), the year it was first drafted (11), the number of document from a list of other central documents local to GOSH and ICH (SOP22) and the current version number (02). The date when it was last amended is found in the footer. (2) DEFINITIONS a) Fraud: can be defined as criminal deception or dishonest artifice or trick. Fraud should not be confused with clinical research of poor quality. b) Serious Breach of GCP: A serious breach of the principles of GCP that is likely to affect to a significant degree, the safety or physical or mental integrity of the subjects of the trial; or the scientific value of the trial. c) Serious Breach of trial protocol: A serious breach of the trial protocol that is likely to affect to a significant degree, the safety or physical or mental integrity of the subjects of the trial or the scientific value of the trial. (3) SCOPE Regulation 29A of the UK Medicines for Human Use (Clinical Trials) Regulations 2004; Statutory Instrument 2004/1031, as amended by Statutory Instrument 2006/1928, contains a requirement for the notification of serious breaches of GCP or the trial protocol to the MHRA. This SOP outlines the procedure for managing such breaches in Clinical Trials of Investigational Medicinal Products (CTIMPs) sponsored by Great Ormond Street Hospital for Children NHS Trust, or where the CTIMP is conducted at the Trust, whereby the Trust is a participating site. If the Trust as a participating site has been delegated the responsibility of managing serious breaches of GCP or trial protocol then either this SOP or the s SOP (as per the Clinical Trial Agreement) should be used to ensure correct procedures are followed under the required timeframes. The should be notified in all instances. The Senior Research Governance Coordinator in the Joint R&D Office should be notified to ensure: oversight, compliance with responsibility (where applicable), and that patient safety and trial integrity has not been compromised. (4) LEGAL BASIS The legal basis for this OP is EU Directive 2001/20/EC1 published in 2001 (also known as Clinical Trials Directive) which establishes specific provisions regarding the conduct of clinical trials, in particular relating to the implementation of Good Clinical Practice (GCP). In the UK it is implemented by Regulations 29A Notification of Serious Breaches of Statutory Instrument 2006 No. 1928: The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 for the UK. (5) ASSOCIATED DOCUMENTS 1. MHRA Notification of Serious Breaches Form Version ) Page 2 of 13

3 2. Form F20: Report of other important safety issues Please review MHRA web-pages on Serious Breaches when using this SOP and MHRA form: ctice/background/index.htm ctice/news/con (6) RESPONSIBILITIES The overall responsibility Notification of Serious Breach in a clinical trial of a medicinal product is with the of the clinical trial. At GOSH/ICH, the is defined as the organisation GOSH: Great Ormond Street Hospital for Children NHS Trust, or UCL - Institute of Child Health (ICH as a Department of UCL). This SOP applies to Clinical Trials of Investigational Medicinal Products (CTIMPs) regulated by the UK regulations on Clinical Trials (The Medicine for Human Use (Clinical Trials) Regulations 2004 and its amendments 2006, 2008 and 2009) and to Chief/Principle Investigators and their team, trial monitors, auditors and staff of the Joint R&D Office who may identify a serious breach of GCP or the protocol. (7) PROCEDURE Serious breach of GCP and/or protocol The procedure for notification of serious breaches of GCP or the trial protocol can be divided into 4 key areas: 1. Identifying and notifying the of a serious breach 2. Assessment of a serious breach 3. Notification to the MHRA and Research Ethics Committee (REC) and provision of additional information to the MHRA and Research Ethics Committee 4. Planning and Implementing Corrective and Preventive Actions A breach of GCP and/or protocol is defined as serious when it is likely to affect 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 Examples of Serious Breach Proof of fraud relating to clinical trial records or data. Persistent or systematic non-compliance with GCP or protocol that has a significant impact on the integrity of trial subjects in the UK or on the scientific value of the trial. Failure to control investigational medicinal product(s) such that trial subjects or the public in the UK are put at significant risk or the scientific value of the trial is compromised. Page 3 of 13

4 Failure to report Adverse Events, Serious Adverse Events or SUSARs in accordance with the legislation, such that trial subjects, or the public, in the UK are put at significant risk. Note: Refer Appendix 2 for more detailed examples 7.1 Identification and Notification of a Serious Breach to Not all breaches from protocol will be considered to be serious. However, all deviations/violations from the approved protocol should be documented by researchers by completion of Form F20: Report of Other Important Safety Issue, and send it to the Joint R&D Office for review and a copy should be filed in the Trial Master File/Investigator File Breaches can be identified by anyone who is conducting, managing or monitoring the trial. It is the responsibility of the person who identifies a suspected serious breach of GCP and/or protocol to notify the Joint R&D Office Upon identification of a protocol/gcp breach, the Chief/Principal Investigator determines how the breach impacts on the subject/patient safety The judgement on whether a breach is likely to have a significant impact on the scientific value of the trial depends on a variety of factors e.g. the design of the trial, the type and extent of the data affected by the breach, the overall contribution of the data to key analysis parameters, the impact of excluding the data from the analysis etc All suspected serious breaches MUST be notified to the Joint R&D Office within 24 hours of the breach being identified Reporting can be by or in person and should provide details of the trial, the CI/PI of the site, how the breach was identified and full details of the breach, assessment of impact of the breach to subject safety and/or scientific integrity of trial and details of corrective action taken (if already taken) The Joint R&D Office staff member who receives notification of the breach should immediately inform a Clinical Trials Co-ordinator. 7.2 Assessment of Serious Breach It is the responsibility of the (Joint R&D Office) to assess the impact of the breach on the scientific value of the trial. This assessment will be documented and the appropriateness of the decisions taken by the can be examined during MHRA inspections Upon receipt of the initial report the Clinical Trials Manager/Senior Industry Manager in the Joint R&D Office will: Promptly discuss with relevant research team to confirm the seriousness of the breach. If unclear about the potential for a breach to have significant impact on the scientific value of the trial, contact the MHRA to discuss the issue. Collect any further documentation/supporting evidence. In the case of studies sponsored by the Trust, agree with the CI any remedial actions to be taken if the breach does not warrant notification to the MHRA and REC. Page 4 of 13

5 In the case of studies where the trust is a participating site, agree with the PI whether the and REC should be notified of the breach The final decision of whether the breach meets serious breach of GCP and/or protocol will be made by the Senior Industry Manager and/or the Clinical Trials Manager, and where necessary escalated to the Deputy Director of Research and Innovation and the Director of Clinical R&D. Documentation of the review of all associated documents and the final decision must be signed and dated and filed within the relevant R&D file and Trial Master File Clinical Trials Manager will assess the breach in collaboration with the CI/PI to introduce any urgent safety measures if required. 7.3 Notification of Serious Breach to MHRA and Research Ethics Committee and provision of additional information to the MHRA and Research Ethics Committee (Trust sponsored CTIMPs) If it is clear that a serious breach has occurred in a study sponsored by the Trust, the MHRA must be informed within 7 days of the (the Joint R&D Office) becoming aware of the serious breach. This can be done by telephone initially, followed up by written notification Clinical Trials Manager/Co-ordinator in the Joint R&D Office will complete the Notification of a Serious Breach of GCP or the Protocol Form (Appendix 1) Clinical Trials Manager/Co-ordinator in the Joint R&D Office will send the form by to the MHRA (GCP.SeriousBreaches@mhra.gsi.gov.uk ) within 7 days of the Trust (the Joint R&D Office) becoming aware of the serious breach Any further information required by the MHRA will be provided by the Joint R&D Office and/or the CI/PI when requested. 7.4 Planning and Implementing Corrective and Preventive Actions The Principal Investigator at the relevant study site will collaborate with the Chief Investigator and the (the Joint R&D Office) to devise a formal plan of corrective and preventive action to address the breach in a timely manner Any corrective and preventative measures should be implemented as appropriate. If urgent safety measures have been taken, these should be notified to the MHRA and REC by the (the Joint R&D Office) within 3 days of the action taken All correspondence and documentation relating to the breach should be retained in the TMF, Investigator and R&D files. (8) RECORDS All serious breaches of GCP or protocol records originating from GOSH/ICH sponsored CTIMPs and generated from this procedure will be filed within the s R&D File under the Pharmacovigilance section with a copy filed in the Chief Investigator s site files. The s R&D File forms part of the essential documents that will be archived with the rest of the R&D records, the Chief Investigator s TMF and pharmacy files for that trial as specified in the Operating Procedure OP35. (9) REFERENCES USED IN WRITING THIS DOCUMENT Page 5 of 13

6 1. The Directive 2001/20/EC of the European Parliament and of The Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Official Journal of the European Communities; 1 st May 2001, L121/34 2. The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031) 3. The Medicines for Human Use (Clinical Trials) Amended Regulations 2006 (SI 2006/1928) 4. The Medicines for Human Use (Clinical Trials) Amended Regulations 2009 (SI 2009/1164) 5. MHRA Serious Breaches Guidance Version 2.0 dated 15/10/09 (10) ABBREVIATIONS Abbreviation Master List is saved here: L:\Shared Folders\DOCUMENT CONTROL/OP Abbreviation Master List.doc (11) HISTORY OF DOCUMENT Name of Document Version No: Date Author Approved by Reason for change GOSH/ ICH/11/S21/ st Aug 2011 Biren Patel Dr Lorna Gibson First Issue GOSH/ ICH/11/S21/ Feb 2014 Praseeda Thaikalloor Emma Pendleton Annual update and minor change Page 6 of 13

7 APPENDIX 1 MHRA Notification of Serious Breaches of GCP or Protocol Form FOR MHRA USE ONLY: GCP Unique ID: Triaging Inspector Notification of Serious Breach of Good Clinical Practice or Trial Protocol (Ref: UK Statutory Instrument 2004/1031 Regulation 29A, as amended by 2006/1928) Please forward this notification to GCP.SeriousBreaches@mhra.gsi.gov.uk OR GCP Inspectorate, MHRA, 2a Hunter house, 57 Goodramgate, York, YO1 7FX. Your Name: Your Organisation: Your Contact Details: Date Breach Identified by : Date Breach Notified to MHRA: Details of Individual or Organisation committing breach: Details of related study (if applicable): (e.g. EudraCT No, CTA number, study title) Report: Tick appropriately Initial Report Follow-up Report Please give details of the breach Potential impact to patient safety and/or data credibility: Patient safety Scientific value / data credibility Patient confidentiality NA/None Approval Issues Other Non-compliances (specify) IMP Background: (continue on additional sheets if required) Other relevant information: (i.e. study status, site(s), ethics, trust, CRO /sponsor details etc.) Page 7 of 13

8 (continue on additional sheets if required) Page 8 of 13

9 Please give details of the action taken: This should include: Any investigations by your organisation, details of investigations by other organisations (e.g. CRO/ethics/trust), the results and outcomes of the investigations (if known or details of when they will be available/submitted), how it will be reported in the final report/publication, the corrective & preventative action implemented to ensure the breach does not occur again. (continue on additional sheets if required) Actual impact to patient safety and/or data credibility: Patient safety Scientific value / data credibility Patient confidentiality NA/None Approval Issues Other Non-compliances (specify) IMP Page 9 of 13

10 APPENDIX 2 Notification examples from MHRA Serious Breach Guidance document Notifier Breach Is it considered a Serious Breach? Contractor Identified during inspection Dosing error. Research Ethics Committee & MHRA informed. Subjects withdrawn. The stated that there were no serious consequences to subjects or data. Patient Information Leaflet and Informed Consent updated. At one trial site this was not relayed to the patients until approximately 2-3 months after approval. More information on the potential consequences of the delay should have been provided. Visit date deviation. A common deviation in clinical trials. Investigator failed to report a single SAE as defined in the protocol (re-training provided). Investigator site failed to reduce or stop trial medication, in response to certain laboratory parameters, as required by the protocol. This occurred with several patients over a 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 in the UK, which did not affect the overall scientific value of the s trial or the integrity of trial subjects in the UK. However, the is aware that the investigator site was also involved in trials being sponsored by other organisations. No As no significant impact on the integrity of trial subjects or on scientific validity of the trial. Possibly not. If this was not a systematic or persistent problem and if no harm to trial subjects resulted from the delay. Yes, if there was a significant impact on the integrity of trial subjects (e.g. there was key safety information not relayed to subjects in a timely manner etc.). No Minor protocol deviation, which does not meet the criteria for notification. No, if it did not result in this or other trial subjects 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. Yes Although, in this situation, not a legal requirement under 29A, MHRA encourages voluntary reporting of all fraud cases in the UK, because MHRA will need to establish the impact on the other trials in case subject integrity or the scientific value of those trials was compromised. Page 10 of 13

11 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 IMP found to have become unstable and this resulted in harm or potential harm to subjects. (s) MHRA (CTU) CRO On two separate occasions, s have identified issues with the same organisation. First with consenting issues and the second with potential fraud in recruitment and consenting. However, there was not unequivocal evidence of fraud at the time of reporting. One of the studies involved children. The GCP Inspectorate notified that a substantial amendment had been submitted regarding changes to dosing on a first in human study, as a result of an SAE after dosing the initial subject. The had temporarily halted the trial and only after further investigation had assigned the SAE as unrelated. The had not notified the CTU of the urgent safety measure implemented or reported the SAE as a potential SUSAR. A cohort had invalid blood samples as they were processed incorrectly. As a result one of the secondary endpoints could not be met. Therefore, a substantial amendment was required to recruit more subjects to meet the endpoint. Patients were dosed unnecessarily as a result of this error. A pharmacy dispensing error resulted in a non-serious adverse event. The incident was investigated and the notification from the confirmed that training had occurred and more robust procedures were being Page 11 of 13 Yes, this subsequently led to enforcement action against the organisation in question. Yes Yes No, information provided by the identified this as a single episode and the supplied detailed corrective and preventative action. Yes, if it was persistent and systematic, occurring after the CAPA

12 Identified during inspection NRES Member of public implemented by the site. A potential serious breach was identified, but not reported (i.e. documentation in the s TMF identified that there may have been fraud at an investigator site, re-use of previous time point data in later time points). The had investigated and the issue was subsequently found to be a genuine error not fraud. Destruction of investigator site files early (i.e. one study had only been completed a year earlier and one study was still ongoing.) Concerns raised during monitoring visits about changes to source data for a number of patients in a trial, which subsequently made patients eligible with no explanation. An audit was carried out by the and other changes to source data were noted without explanation, potentially impacting on data integrity. Follow-up reports sent to MHRA confirmed concerns over procedures for approvals, consenting issues and data changes made to source without adequate written explanation. A member of public received named invite to be a volunteer in clinical trials (no specific trial mentioned). However, she was not on the organisation s volunteer database and had not participated previously in a study. On further investigation by MHRA, the organisation had contracted the use of a mail-shot organisation to send a generic mail-shot to a list of people in relevant area over a certain age. This had been approved by the Research Ethics Committee. A study patient attended A&E, who attempted to contact pharmacy (using the phone number on the patient s emergency card) in order to break the un-blinding code. Unable to break code in a timely manner, and the patient had been put in place by the. No, on this occasion. However, had this been identified as fraud impacting on the integrity of the data, then this serious breach would not have been notified within the regulatory timeframe (i.e. 7 day window). Yes Yes Note: not all information provided in original notification and provided follow-up updates. No Yes, as this could have resulted in significant potential to harm to the subject if un-blinding would have affected the course of treatment. Page 12 of 13

13 CRO decided to withdraw from the study feeling unhappy that the pharmacy was not available for emergency situations. Patient safety compromised as, protocol not followed and, therefore, repeat ECGs were not conducted when required. Also potential stopping criteria missed due to inadequate QC of the interim clinical summary report for dose escalation. Yes Page 13 of 13