Standard Operating Procedure for the Preparation and Submission of Development Safety Update Reports

Transcription

1 S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Sponsor SOPs\SPON_S31 SOPs on DSUR\SPON_S31_SOP on DSUR_V02.doc Page 1 of 12 Standard Operating Procedure for the Preparation and Submission of Development Safety Update Reports SOP ID Number: Effective Date: 12/12/13 Version Number & Date of Authorisation: V02, 07/11/13 Review Date: 12/12/16 edocument kept: S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Sponsor SOPs\SPON_S31 SOPs on DSUR\SPON_S31_SOP on DSUR_V02.doc Page 1 of 12

2 S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Sponsor SOPs\SPON_S31 SOPs on DSUR\SPON_S31_SOP on DSUR_V02.doc Page 2 of 12 Revision Chronology: SOP ID Number: Effective Date: Reason for Change: Author: JBRU/SPON/S31/01 19/07/11 12/12/13 New SOP Deletion of Safety Committee Research Fellow from the review process and DSUR template. Update to DSUR workflow, inclusion of RSI process and for process to be used when trial has not opened to recruitment. Farhat Gilani Farhat Gilani ACRONYMS: ASR Annual Safety Report CI Chief Investigator DIBD Development International Birth Date DSUR Development Safety Update Report GCP Good Clinical Practice IMP Investigational Medicinal Product ISF Investigator Site File JRO Joint Research Office MHRA Medicines and Healthcare Products Regulatory Agency MREC Main Research Ethics Committee PI Principal Investigator QA Quality Assurance RM Regulatory Manager Advanced Therapy Trials RSI Reference Safety Information SRA Sponsor Regulatory Advisor SOP Standard Operating Procedure TMF Trial Master File Page 2 of 12

3 S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Sponsor SOPs\SPON_S31 SOPs on DSUR\SPON_S31_SOP on DSUR_V02.doc Page 3 of 12 Standard Operating Procedure for the Preparation and Submission of Development Safety Update Reports 1. PURPOSE This Standard Operating Procedure (SOP) has been written to describe the procedure for the production and submission of the Development Safety Update Report (DSUR) to the MHRA and Ethics Committee. For international trials, reference on DSUR production and submission will be detailed in contractual agreements and/or specific protocol documents. 2. JOINT RESEARCH OFFICE POLICY All SOPs produced from the JRO must be used in conjunction with local NHS Trust and UCL policies and procedures. The JRO acts as the representative of the sponsor and will be the official name used on all SOPs. 3. BACKGROUND All SOPs are written in accordance with applicable GCP requirements as outlined in Directives 2001/20/EC and 2005/28/EC (in the UK, these Directives were transposed into UK law by SI 2004/1031, SI 2006/1928) and subsequent amendments and where applicable incorporates elements of ICH GCP tripartite guidelines (E6). The Medicines for Human Use (Clinical Trials) Regulations 2004 and subsequent amendments regulate Clinical Trials in the UK and set out the legal requirements for the production of Annual Safety Reports (ASR). To comply with the UK regulations, sponsors need to provide procedures and systems to support the production and submission of this safety document. The Development Safety Update Report (DSUR) Guidance (ICH E2F) was published in the European Union in September 2010 and implemented in September The DSUR replaces the regulatory requirement for the Annual Safety Report (ASR) format and content (Regulation 35 of SI 2004/1031, p34) but does not affect reporting timelines. Sponsors are required to submit a DSUR report to the MHRA and the Ethics committee, once a year, throughout the life of a clinical trial or on request from the MHRA. This DSUR should take into account all new safety information received during the reporting period for the IMP, which may be used in other UCL sponsored trials, not just for a specific trial. 4. SCOPE OF THIS SOP This SOP relates to the process to facilitate the production and submission of the DSUR. It will outline the key responsibilities of all personnel involved and detail the interactions required to ensure the report is produced adequately and submitted to meet regulatory timelines. Page 3 of 12

4 S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Sponsor SOPs\SPON_S31 SOPs on DSUR\SPON_S31_SOP on DSUR_V02.doc Page 4 of RESPONSIBLE PERSONNEL CI (CTIMPs) or trial team members with delegated duties regarding the production of the DSUR IMP specific trial team members for mechanistic studies Pharmacovigilance Manager or SRA, Sponsor RMG Senior Research Coordinators, Sponsor 6. PROCEDURE Please ensure that you are using the most recent SOP version by looking up Periodicity and DSUR data lock Point The Development International Birth Date (DIBD) is used to determine the start of the annual period for the DSUR. This date is the sponsor s first authorisation to conduct a clinical trial in any country worldwide. The start of the annual period for the DSUR is the month and date of the DIBD. The data lock point of the DSUR should be the last day of the one-year reporting period. The DSUR should be submitted to all concerned regulatory agencies no later than 60 calendar days after the DSUR data lock point If a trial has received a CTA approval and has not yet opened to recruitment at DIBD then a cover letter may replace the DSUR detailing any safety updates that have occurred. The cover letter should also include the EudraCT number and trial title DSURs should continue to be submitted until the End of Trial notification has been submitted for UK trials. For International trials this will be dependant on their applicable laws and regulations. When submission of an annual report is no longer required, the sponsor should state that the final DSUR serves as the last annual report of the IMP (if this is known at the time of preparation of the report). The Sponsor should also indicate whether or not clinical trials are continuing elsewhere The sponsor will endeavour to inform the trial team of the DIBD date if it is different from the CTA approval date either at trial initiation or at the DIBD data lock point. 6.2 DSURs for combinations therapies DSURs are IMP specific therefore for trials involving multi-drug therapy, i.e., combinations of drugs that are not fixed, the Sponsor, in conjunction with the CI will decide to prepare either: (1) A DSUR for the multi-drug therapy, or (2) DSUR(s) for one or more of the individual components; in this case information on the multi-drug therapy trials can be included in the DSURs of one or all of the components. The following table provides examples of strategies for preparation of DSURs for multidrug therapies. Page 4 of 12

5 S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Sponsor SOPs\SPON_S31 SOPs on DSUR\SPON_S31_SOP on DSUR_V02.doc Page 5 of 12 Multi-drug therapy used in clinical trial(s) DSUR Investigational drug (A) + marketed drug(s) (X, Y, Z) Either a single DSUR focusing on (A+X+Y+Z) or A single DSUR focusing on (A) including data on the multi-drug therapy Two investigational drugs (A) + (B) Either a single DSUR focusing on (A + B) or Two separate DSURs (A) and (B), each including data on the multi-drug therapy Two (or more) marketed drugs as an investigational drug combination (X, Y, Z) A single DSUR focusing on the multidrug therapy In general, a single DSUR should be prepared for clinical trials involving a fixed combination product (i.e., a product consisting of at least two active ingredients in a fixed dose that is administered in a single dosage form). If the sponsor is also conducting clinical trials with individual component(s) of the fixed combination product, separate DSUR(s) should be submitted for each component. Relevant findings from each DSUR should be summarized in Section 8.5 of the other DSUR(s) The sponsor in conjunction with the CI will select the most appropriate, option based on judgment, taking into account patient population, indication, formulation, etc., as well as the circumstances in which the clinical trials are being conducted and national or regional laws or regulations. The rationale for this decision should be provided in the report The Sponsor will endeavor to inform the trial team of the DSUR format at trial initiation or at the DIBD data lock point. 6.3 Responsibilities for the Preparation and submission of a DSUR All DSURs must meet the standard that adheres to the EUCTD (2001/20/EC) and the UK trials regulations SI 2004/1031. The Sponsor has prepared a template (Appendix 1) which meets these requirements and all sponsored trials must use this document (unless stated otherwise in contractual agreements) The Sponsor is considered responsible for the preparation, content and submission of the report. Preparation of various sections of the DSUR is delegated to individuals as listed below. However, the collation, final sign off and submission is performed by members of the JRO (unless stated otherwise in individual contractual agreements) The Sponsor will coordinate the preparation of the document by ing requests for various sections of information to all relevant individuals (see Appendix 1 for workflow diagram). On receipt, the information will be amalgamated into the DSUR template by the Sponsor Page 5 of 12

6 S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Sponsor SOPs\SPON_S31 SOPs on DSUR\SPON_S31_SOP on DSUR_V02.doc Page 6 of 12 Individuals Tasks SRA, PVG Manager (Sponsor) Coordination and collation of document Final sign off Contents Submission of Report Executive Summary Trial Chief Investigator(s) / Trial Team Trial specific safety information Literature searches Risk-Assessment Conclusion RMG SRA (Sponsor) Mechanistic Trial Information Mechanistic Trial Chief Investigator Trial specific Safety Information 6.4 Reference Safety Information (RSI) The RSI for a CTIMP is either detailed in the IB or SPC and is submitted as part of the CTA application. The RSI for any IMPs involved in a clinical trial must stay consistent during each DSUR reporting period. The RSI at the time of the beginning of reporting period will be used When the IMP and therefore IB are produced by UCL it is recommended submitting an IB with a RSI update in conjunction with a DSUR submission, as the information within the DSUR will act as a justification for the changes When the IMP is provided directly from a commercial sponsor, UCL should negotiate transfer of trial information thereby allowing a single DSUR being produced for that product by the commercial sponsor. If this is not possible the following table should be used to ensure the correct IB information is incorporated into the DSUR. Process for IB updates from commercial and UCL manufacturers Approval/amendments IB Comments DSUR submission comments DSUR 1 Initial IB If not updated within the reporting period for the first DSUR Substantial amendment of IB Updated IB approved by MHRA prior to being implemented The DSUR for that year will use the previous version of the IB with regards to the RSI (approved at the beginning of the DIBD date) and will detail the new IB in the DSUR. The newly approved IB will be used for the following year DSUR production. Non-Substantial amendment of IB The updated IB can be implemented immediately The DSUR for that year will use the previous version of the IB (approved at the beginning of the DIBD date) and will detail the new IB in the DSUR. The newly approved IB will be used for the following year DSUR production. Page 6 of 12

7 S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Sponsor SOPs\SPON_S31 SOPs on DSUR\SPON_S31_SOP on DSUR_V02.doc Page 7 of Process for SmPC updates If the RSI is within the SmPC, the list of expected adverse reactions is contained in section 4.8 Undesirable Effects. For trials where a SPC is used as the RSI the updates are managed by the IMP manufacturer. When the JRO are made aware of an SmPC update it will be reviewed: To see if the safety profile of the IMP has been altered and impacts on trial process and patient safety (new contraindicated drugs, dosing levels altered etc.) To see if the RSI (expectedness) has been changed. CT3 states SUSARs must be assessed against the RSI at time of occurrence of the adverse event. Within a DSUR reporting period, the RSI may be updated and an unexpected event becomes expected. At the time of DSUR production the expectedness of events that have occurred in the reporting period will be reassessed against the RSI at the beginning of the reporting period. The RSI used to assess expectedness and any subsequent updates will be attached as appendices and clearly detailed in the DSUR. 6.5 Submission Procedures The DSUR will be submitted to both the MHRA and REC by the Sponsor. For international trials and trials where this responsibility is delegated to another organisation or to the trial team, a final signed copy must be sent to the Sponsor The DSUR should be signed by the person submitting the report and should be submitted in pdf to the MHRA and on paper to the REC. All enclosures should be listed and referenced on the report For the REC submission a standard cover sheet must also be submitted which is available from the NRES website: If a DSUR is being submitted late to the regulatory agencies, a cover letter must also be sent from the sponsor detailing the reason for the late submission A copy of the DSUR will be forwarded to the CTIMP CI(s) to be filed in the TMF If an unblinded DSUR is prepared by the sponsor, a separate final blinded copy will be forwarded to the CTIMP CI(s) if the blind has not been broken. 7. REFERENCES ICH Harmonised Tripartite Guideline for Development Safety Update Report E2F ICH Harmonised Tripartite Guideline for Good Clinical Practice (1996) E6 The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 1031) The Clinical Trials Directive 2001/20/EC 8. TEMPLATES/LOGS ASSOCIATED TO THIS SOP 1 DSUR workflow 2 DSUR template Page 7 of 12

8 S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Sponsor SOPs\SPON_S31 SOPs on DSUR\SPON_S31_SOP on DSUR_V02.doc Page 8 of DSUR work flow Estimated Timelines and workflow, for the Preparation and Submission of DSURs by the Sponsor s office, for trials managed by CIs (not for CTU managed trials). -30 Days to Day 0 0 Days DIBD Date +30Days +45 Days +60 Days Collate information from: Mechanistic Information Trial Specific Information (e.g. Urgent Safety Measures in Sponsor TMF) IMP Specific Information Review IB/SmPC changes sent to CI approximately within 2 week +/- of Day 0 With any new documents from searches. Requesting literature search and results. Update of trial relevant trial status Incorporate ALL information into the DSUR Final QC check by Sponsor Submitted to MHRA REC CI(s) Page 8 of 12

9 S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Sponsor SOPs\SPON_S31 SOPs on DSUR\SPON_S31_SOP on DSUR_V02.doc Page 9 of SOP DISSEMINATION AND TRAINING SOPs will be distributed to the concerned staff, by the named author on the front page of the SOP. Staff concerned by the SOP will sign the SOP training log (12. SOP TRAINING LOG) which is part of each SOP. In some instances, the SOP or the changes to the SOP will be basic. The training will constitute of the person reading the SOP and being provided with the opportunity to ask specific questions to the author of the SOP. In some instances, the staff member being trained will carry out the procedure under supervision of the author of the SOP or under supervision of a staff member who has been trained and is using the SOP. Both trainee and trainer (should the SOP require training) will need to sign and date the SOP training log in section 12 of each SOP. 10. SIGNATURE PAGE Author and Job Title: Farhat Gilani, Pharmacovigilance Manager Signature: Date: 07/11/13 Authorised by: Name and Job Title: Helen Cadiou, Quality Assurance Manager Signature: Date: 07/11/13 Page 9 of 12

10 S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Sponsor SOPs\SPON_S31 SOPs on DSUR\SPON_S31_SOP on DSUR_V02.doc Page 10 of SOP TRAINING LOG 1 Name of Staff (Capital letters) Job Title: Department: Training Date I confirm that I understand & agree to work to this SOP SIGNATURE Name of Trainer (if training required) Signature Date Page 10 of 12

11 S:\_SLMS\RSC_ALL_STAFF\CLINICAL_TRIALS\SOPs\EFFECTIVE_SOPs_Guides\Sponsor SOPs\SPON_S31 SOPs on DSUR\SPON_S31_SOP on DSUR_V02.doc Page 11 of 12 8 Name of Staff (Capital letters) Job Title: Department: Training Date I confirm that I understand & agree to work to this SOP SIGNATURE Name of Trainer (if training required) Signature Date Page 11 of 12

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