NEWCASTLE CLINICAL TRIALS UNIT STANDARD OPERATING PROCEDURES

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1 NEWCASTLE CLINICAL TRIALS UNIT STANDARD OPERATING PROCEDURES SOP details SOP title: Safety Reporting in CTIMPs and ATMPs SOP number: TM-003 SOP category: Trial Management Version number: 04 Version date: 10 July 2017 Effective date: 10 August 2017 Revision due date: 10 August 2020 SOP author details Author name: Author position: Author signature: Date: Joan Farrington Deputy Quality Assurance Manager This electronic version is uncontrolled. The signed controlled copy is held in the Newcastle Clinical Trials Unit. SOP authoriser details Authoriser name: Authoriser position: Authoriser signature: Date: Jill Peacock Quality Assurance Manager This electronic version is uncontrolled. The signed controlled copy is held in the Newcastle Clinical Trials Unit. STATEMENT This is a controlled document. The master document is held within NCTU with a controlled copy posted on the NCTU website: Any print-off of this document will be classed as uncontrolled and should not be filed. The reader is responsible for regularly checking the NCTU website for more recent versions. SOP NCTU: TM-003 Version: 04 Version date: 10 JUL 2017 Page 1 of 12

2 SOP revision record Version number Date Reason for revision September 2011 Document release September 2013 Document revision August 2016 Update to include information on RSI, the expected procedures to be completed within NCTU and responsibilities July 2017 Section updated to clarify the criteria for deciding the timeframe for recording of AEs and the requirement for SAR reporting until study close. Section added to outline the requirement for documented review of causality and expectedness of SAEs by the CI on behalf of sponsor. Table of Contents 1. BACKGROUND PURPOSE SCOPE ROLES & RESPONSIBILITES ACRONYMS PROCEDURE Standard definitions Study set-up and safety considerations AE recording and reporting requirements Risk assessment RSI Reporting and recording AEs Receipt and follow up of serious adverse events Documented review of SAEs by the CI on behalf of sponsor Pregnancy SAE reconciliation SUSAR reporting Reporting a SUSAR within NCTU Blinded studies Non-IMP Investigator notification Regular reports SOP NCTU: TM-003 Version: 04 Version date: 10 JUL 2017 Page 2 of 12

3 Development Safety Update Report Trial Oversight Committee reports Advanced Therapy Medicinal Products Expedited reporting Follow up REVIEW AND MONITORING OF THIS DOCUMENT ASSOCIATED DOCUMENTS BACKGROUND Patient safety should always be paramount during research. It is essential that any Adverse Events (AEs) or safety issues that occur during a research project are appropriately managed, reviewed and followed up to ensure the continuing safety of study participants. For Clinical Trials of Investigational Medicinal Products (CTIMPs) there is a legal requirement for the management and reporting of AEs in accordance with the Medicines for Human Use (Clinical Trials) Regulations The regulations set out the requirements for notification and reporting of AEs and adverse reactions (ARs) during a CTIMP. There are additional requirements for clinical trials of Advanced Therapy Medicinal Products (ATMPs) outlined in Detailed guidelines on good clinical practice specific to advanced therapy medicinal products, PURPOSE The purpose of this Standard Operating Procedure (SOP) is to describe the processes to be followed for assessing, recording, notifying and reporting safety information in accordance with the regulatory requirements for CTIMPs and ATMPs. 3. SCOPE This SOP applies to all personnel within Newcastle Clinical Trials Unit (NCTU) involved in any aspect of safety reporting, including trend analysis. The procedures within the SOP apply when NCTU has been delegated the duty of safety reporting and pharmacovigilance on behalf of the research sponsor. It is the responsibility of the Trial Manager to refer to the agreement with the sponsor to determine the responsibilities of NCTU with respect to safety reporting. This SOP does not include Urgent Safety Measures which are covered in NCTU SOP TM ROLES & RESPONSIBILITES The sponsor is responsible for the ongoing safety evaluation of the Investigational Medicinal Product (IMP) or ATMP however may delegate these tasks to the Chief Investigator (CI) or NCTU. SOP NCTU: TM-003 Version: 04 Version date: 10 JUL 2017 Page 3 of 12

4 Specific roles and responsibilities are covered in the relevant sections of the SOP however, as a rule it is the responsibility of the Trial Manager to ensure compliance with the regulations. The Trial Manager may delegate specific tasks to other personnel, e.g. a clinical trial administrator, however must retain oversight of these tasks. Safety trend analysis and overarching review of safety data is the responsibility of the Data Monitoring Committee or Trial Oversight Committee where applicable. All parties are responsible for ensuring they observe a duty of care with regards to patient safety and related reporting. 5. ACRONYMS AE AR ATMP CESP CI CTIMP DIBD DSUR esusar IMP MHRA NCTU NIMP PI QA REC RSI SAE SAR SOP SUSAR Adverse Event Adverse Reaction Advanced Therapy Medicinal Product Common European Submission Portal Chief Investigator Clinical Trial of an Investigational Medicinal Product Development International Birth Date Development Safety Update Report electronic Suspected Unexpected Serious Adverse Reaction reporting system Investigational Medicinal Product Medicines and Healthcare products Regulatory Agency Newcastle Clinical Trials Unit Non-Investigational Medicinal Product Principal Investigator Quality Assurance Research Ethics Committee Reference Safety Information Serious Adverse Event Serious Adverse Reaction Standard Operating Procedure Suspected Unexpected Serious Adverse Reaction 6. PROCEDURE 6.1 Standard definitions Term Adverse Event Definition Any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product. SOP NCTU: TM-003 Version: 04 Version date: 10 JUL 2017 Page 4 of 12

5 Adverse Reaction Causality Expected Reference Safety Information (RSI) Sequelae Serious Suspected Unexpected Serious Adverse Reaction (SUSAR) Severity Unexpected Any untoward and unintended response in a subject to an IMP which is related to any dose administered to that subject. The assessment of the root cause of an AE to determine if the IMP(s) under study was a factor. An AR/Serious AR that has been included in the approved Reference Safety Information. The RSI is the list of known side effects of the IMP(s) under study and the information used to assess the expectedness of an AR/Serious AR. A condition following or occurring as a consequence of another condition or event. An AE or AR is serious if it meets one of the following criteria: results in death is life-threatening (i.e. the participant was at risk of death at the time of the event rather than an event that hypothetically might have caused death if it were more severe) requires hospitalisation or the prolongation of existing hospitalisation results in persistent or significant disability or incapacity is a congenital anomaly or birth defect; or is medically important (i.e. the event jeopardised the immediate health of the participant or required intervention to prevent event becoming serious) Any AR that is classed as serious and unexpected. The scale of determining the grade of the event e.g. mild, moderate and severe. Severity is not the same as seriousness and an AE can be severe without meeting the criteria of being serious. An AR/Serious AR not included in the RSI or AR/Serious AR that is listed but the frequency or severity of the event is not consistent with the information within the RSI. SOP NCTU: TM-003 Version: 04 Version date: 10 JUL 2017 Page 5 of 12

6 6.2 Study set-up and safety considerations Safety reporting requirements must be considered early during the development of a study and the protocol. It is important to ensure that all relevant parties are included in these discussions, preferably through the Trial Management Group, to ensure the procedures are robust AE recording and reporting requirements Specific requirements/procedures for assessing, recording, notifying and reporting AEs must be clearly defined in the study protocol, including the specific timelines to be followed. This includes details of delegated responsibilities where appropriate. The overarching study timeframe for reporting AEs must also be specified e.g. to record AEs from point of consent or from point of study intervention. AE recording may stop at the end of treatment or follow up and the timeframe should be defined in the protocol based on the half-life of the IMP and the expected duration of pharmacodynamic action. However, any Serious Adverse Reaction (SAR) that comes to the attention of the site team must be recorded and reported up until the point of study closure. Certain events which meet the criteria of serious may be exempted from SAE reporting in certain circumstances however this must be justified through the risk assessment for the study. Any events which are exempted from SAE reporting should be specified in the protocol Risk assessment RSI A documented risk assessment must be conducted, prior to obtaining the research approvals, to define the level of safety monitoring and reporting required for each study. Lower risk studies with a known safety profile may just require the recording of SAEs or it may be appropriate to exclude SAE recording of those expected events that are recorded and monitored as outcome measures. The level of safety monitoring and reporting determined by the risk assessment must be authorised by the sponsor prior to implementation. The risk assessment must also include an assessment of the risk of the IMP passing to the embryo or foetus in the event that a study participant, or partner of a study participant, becomes pregnant during the study. Acceptable contraceptive measures must be described in the protocol as well as the process to be followed in the event that a participant, or their partner, becomes pregnant. The RSI is the list of known adverse reactions for the IMP/IMPs under study and must be approved by the Medicines and Healthcare products Regulatory Agency (MHRA) as part of the original Clinical Trial Authorisation or through a substantial amendment in the event of an update to the RSI. Only the approved RSI can be used to assess the expectedness of any SAR that occurs during the trial. It is the sponsor s responsibility to determine the RSI for the trial however, this task may be delegated to the CI. SOP NCTU: TM-003 Version: 04 Version date: 10 JUL 2017 Page 6 of 12

7 In general, the RSI may be a section within the Investigator Brochure (for IMP without a Marketing Authorisation or being used outwith of the current Marketing Authorisation) or the Summary of Product Characteristics (for IMP with a Marketing Authorisation and being used within the licensed indication). However, the CI must take into account the participant population to be studied and the current available information e.g. it is not acceptable to use the list of undesirable effects observed in patients with Chronic Myeloid Leukaemia when the participant population will be unconscious individuals in critical care. There can only be one RSI for each IMP under study. In the event that there may be several lists of undesirable effects from multiple sources, e.g. different generic manufacturers or multiple doses of the same IMP, these must be reviewed and either one chosen as the designated RSI or an amalgamated list prepared for approval by the MHRA as the approved as the RSI. Further information on RSI can be found in the NCTU Reference Safety Information Working Instruction. 6.3 Reporting and recording AEs The requirements for recording and reporting AEs by sites must be included in the protocol. It is the responsibility of designated site personnel to collect and record AEs in accordance with the protocol. This includes ensuring that the information is captured in the participant s medical notes (and any other relevant source data) as part of ongoing clinical care. 6.4 Receipt and follow up of serious adverse events SAEs will be received into NCTU either by fax, fax to system or via . The trial management personnel must ensure that the NCTU Quality Assurance (QA) Manager receives a copy of each SAE, preferably as a member of the SAE distribution list. The sponsor should be consulted as to how they will retain oversight of SAE reporting i.e. through receipt of each individual SAE or through receipt of a periodic report listing the SAEs received during a set time period. This must be documented, preferably through a formal agreement with the sponsor, and this documentation filed in the Trial Master File. The initial report of an SAE may be received via verbal notification but this must be followed by a completed SAE form. Upon receipt, the SAE form should be checked by the trial management personnel for: Completeness is all the necessary minimum information present? Event has an appropriate event term been given? Seriousness does the event meet the criteria of seriousness? Causality has the event been assessed by a delegated, medically qualified member of the study team as having a causal relationship to the IMP(s) under study? Expectedness if a causal relationship is suspected, has the event been assessed by a delegated member of the study team or sponsor and classed as unexpected in accordance with the approved RSI? SOP NCTU: TM-003 Version: 04 Version date: 10 JUL 2017 Page 7 of 12

8 Signatures are the required signatures present and are these by personnel listed as being able to do so on the delegation log? All confirmed SAEs, i.e. those that meet the seriousness criteria, should be logged by the Trial Manager or designee on the trial s safety database, allocated a unique SAE number and a confirmation of receipt returned to the sender. The confirmation of receipt should include the assigned SAE number as well as any requests for missing information or necessary clarifications. The SAE form and related correspondence must be filed in the Trial Master File. SAEs must be followed up by the Trial Manager until resolution even if the affected participant has withdrawn from the trial. An SAE is considered to have resolved if the outcome has been classed as: Completely Recovered Recovered with Sequelae Condition stable and no change anticipated Participant Died Unresolved SAEs must be followed up with the relevant site on a regular basis until completion. The frequency of this follow up will be determined by the circumstances of the individual SAE, e.g. acute versus chronic conditions/events, as well as the design of the study Documented review of SAEs by the CI on behalf of sponsor Each study should have a process in place for documented review by the CI of the PI assessment of causality and expectedness for each SAE reported to NCTU, where this responsibility has been delegated to the CI by the sponsor. An trail is acceptable as documented evidence of this review by the CI, provided that it confirms the CI s opinion on causality and expectedness for each SAE Pregnancy The standard definition of a SAE includes congenital anomalies or birth defects. Pregnancy itself does not constitute a SAE but study participants that become pregnant or aid in the conception of a child must be followed up until at least the culmination of the pregnancy to determine if a congenital anomaly or birth defect has occurred. The follow up period will be determined by the known or suspected potential for the IMP to cause harm to the foetus in accordance with the risk assessment. If the IMP is known to cause congenital anomalies that are not identifiable upon birth then the follow up period must reflect this. Upon notification that a study participant or partner of a study participant is pregnant, the Trial Manager should request that the clinical site staff complete a pregnancy reporting form and this information must be recorded on the pregnancy tracker. Informed consent must be sought from the participant, and their partner if applicable, in order for the pregnancy to be tracked and information on the outcome of the pregnancy obtained. In the event that a congenital anomaly or birth defect does occur, this must be reported as a SAE. SOP NCTU: TM-003 Version: 04 Version date: 10 JUL 2017 Page 8 of 12

9 6.5 SAE reconciliation The Trial Manager must ensure that any reports of pregnancy are notified to the sponsor and CI within 24 hours of receipt. SAE reconciliation should be conducted on a regular basis, unless the study is due to run for a year or less in which case it is acceptable to conduct the SAE reconciliation at the end of the trial. The reconciliation process should involve a review of the information within the SAE report and ensuring this information is consistent with the information held in the study database. The Trial Management Group must determine the data items to be reconciled and how this will be achieved. This should be documented in the Data Management Plan for the study. 6.6 SUSAR reporting SARs that have been classed as unexpected, in accordance with the approved RSI, must be reported to the MHRA and Research Ethics Committee (REC) in accordance with the regulatory timelines: Fatal/life threatening SUSARs: must be reported as soon as possible but no later than 7 calendar days after the sponsor or delegate becomes aware of the event. Any relevant follow-up information must be sought and reported within a further 8 calendar days. Non- fatal and non-life threatening SUSARs: must be reported as soon as possible, but no later than 15 calendar days after the sponsor or delegate has first knowledge of the minimum criteria for expedited reporting. Further relevant follow-up information should be provided within a further 15 calendar days. Day 0 of the reporting timeline starts when the following minimum information has been obtained: a valid EudraCT number a sponsor study number one identifiable coded participant (e.g. participant study number) one identifiable reporter (e.g. Principal Investigator (PI)) one SUSAR one suspect IMP a causality assessment Upon receipt of a potential SUSAR, the Trial Manager must contact the sponsor to determine the appropriate course of action. Where the sponsor retains the duty for reporting SUSARs, the Trial Manager should cooperate fully with the sponsor s process and provide any requested assistance in a timely manner. The Trial Manager must also request a copy of all relevant documentation from the sponsor for filing within the Trial Master File e.g. copy of esusar form, copy of correspondence with the REC etc Reporting a SUSAR within NCTU SOP NCTU: TM-003 Version: 04 Version date: 10 JUL 2017 Page 9 of 12

10 Where NCTU has been delegated the duty for reporting SUSARs, the Trial Manager must contact the NCTU QA Manager to obtain access to the MHRA s electronic SUSAR (esusar) system. In the event that the NCTU QA Manager is not present, access can be granted by the Senior Trial Managers. The Trial Manager must complete the esusar form with input from the CI, relevant PI and research sponsor. Note that the esusar form requests that both the sponsor and CI assess the causality of the event. Once the form has been completed, a draft must be saved and sent to the CI and sponsor representative for review. Comment should be returned within 24 hours. The finalised esusar form must be submitted via the esusar website and a copy printed for filing within the Trial Master File (the system allows a copy of the report to be printed after submission). A PDF copy of the form should also be saved. The Trial Manager must also notify the REC that gave the favourable ethical opinion of the SUSAR within 15 days of becoming aware of the event. Notification should be via and a copy of the completed esusar report must be submitted along with a completed CTIMP Safety Report to REC form to allow the REC to acknowledge receipt. This form does not need to be signed prior to submission. The REC Coordinator will acknowledge receipt of the report within 30 days by signing and returning a copy of the submitted CTIMP Safety Report to REC form. This procedure must be repeated if a follow-up report is submitted with any relevant, additional information. All forms and related correspondence must be filed within the Trial Master File Blinded studies Maintenance of the blind is vital for the integrity of the trial. Systems for expedited and annual safety reporting should, as far as possible, maintain blinding of individual clinicians and of staff involved in the day-to-day running of the trial. Unblinding may be unavoidable if the information is necessary for the medical management of a particular participant. In a placebo controlled CTIMP the assessment of seriousness, causality and expectedness should be made as though the patient was on active drug. Cases considered serious, unexpected and related (i.e. SUSARs) require unblinding and only those events occurring among patients on the active drug must be reported. However, if the participant is found to be on placebo and the event is considered associated with the placebo (e.g. a reaction to an excipient or impurity within the formulation) such cases must also be reported as a SUSAR to the MHRA. In blinded CTIMPs with multiple IMPs (e.g. comparators) those events assessed as being serious and having a possible causal relationship to one of the IMPs under study must be unblinded. Again, those events that meet the fully definition of a SUSAR require expedited reporting. SOP NCTU: TM-003 Version: 04 Version date: 10 JUL 2017 Page 10 of 12

11 All parties must following the process outlined in the protocol for unblinding participants Non-IMP SARs thought to be related to Non-IMP (NIMP) must be expedited if: The event might be linked to either a NIMP or IMP but it is not possible to attribute causality The event may be linked to an interaction between a NIMP and the IMP The reaction due to the NIMP is likely to affect the safety of the trial subjects Investigator notification 6.7 Regular reports The Trial Manager must ensure that all investigators for a study are informed of any SUSAR that occurs in relation to the IMP used in that study or on another study for which the sponsor is responsible. Unless sponsor requirements dictate otherwise, the NCTU SUSAR summary template should be used for notification of SUSARs to PIs. Documentary evidence of the investigator review must be filed within the Investigator Site File e.g. through signing and dating the notification or via reply . Consideration must be given to blinded studies and the format that the notification takes in order to maintain the blind Development Safety Update Report A Development Safety Update Report (DSUR) must be submitted to the MHRA and NHS REC once a year on the anniversary of the Development International Birth Date (DIBD). The Trial Manager must ensure that the report is submitted within 60 days of the end of the reporting period. The Trial Management Group must input into the compilation of the DSUR and the CI must review and authorise the final report before it is ready for submission. The DSUR should also be reviewed by the NCTU QA Manager and sponsor Representative prior to submission via the Common European Submission Portal (CESP) system. Further information on DSURs can be found in the NCTU Development Safety Update Report Working Instruction Trial Oversight Committee reports Regular reports of unblinded data must be compiled and provided to the Data Monitoring Committee or Trial Oversight Committee, as appropriate, to enable the committee to fulfil their responsibilities for patient safety. The Data Monitoring Committee/Trial Oversight Committee should use this information to look for any safety signals that may require further action and this information passed on to the Trial Steering Committee or sponsor directly. SOP NCTU: TM-003 Version: 04 Version date: 10 JUL 2017 Page 11 of 12

12 6.8 Advanced Therapy Medicinal Products Requirements for ATMPs differ from other CTIMPs particularly with regard to expedited reporting and follow up Expedited reporting In addition to those events that meet the criteria of a SUSAR, the following SAEs must also be reported: SAEs associated with trial procedures SAEs associated with product failure including a lack of efficacy of the trial product SAEs related to mandatory concomitant medications SAEs which are deemed a significant hazard to the participant population SAEs due to infection Unexpected reactions SAEs due to medical devices that form part of the product or used to deliver the ATIMP All such SAEs must be reported to the MHRA as described in section Follow up The duration and nature of follow up should be determined by a risk assessment of the current knowledge of the ATMP, its mode of action and the risk to close contacts as well as offspring. Advice can be sought from the MHRA as to the period and type of follow up expected. 7. REVIEW AND MONITORING OF THIS DOCUMENT This SOP will be reviewed every three years unless there is a change to the applicable legislation or significant revision to the process contained in the SOP. Compliance with this SOP will be monitored through Senior Trial Manager oversight at regular scheduled 1:1 meetings with Trial Managers and through a standing pharmacovigilance agenda item at Trial Management Group Meetings. In addition, compliance with the requirements of this SOP will be assessed through the annual internal audit schedule. 8. ASSOCIATED DOCUMENTS NCTU Development Safety Update Report Working Instruction NCTU Reference Safety Information Working Instruction NCTU Processing Serious Adverse Events Guidance Document SOP NCTU: TM-003 Version: 04 Version date: 10 JUL 2017 Page 12 of 12