Trial name: HOVON xxx yyy Sponsor: HOVON Version history Version number Version date Effective date 01 dd-mon-yyyy dd-mon-yyyy 02 dd-mon-yyyy dd-mon-yyyy 03 (current) dd-mon-yyyy dd-mon-yyyy QRMP authors Name Role Principal Investigator Trial Manager Statistician Central Data Manager Monitor QRMP approval by sponsor Name Role Signature Page 2 of 28
Completion guideline Table 1 - Risk assessment Quality Risk Management Plan HOxxx Table 1 contains a pre-defined list of trial aspects to consider during risk assessment. Trial specific items may be added to the list, but pre-defined aspects should not be removed from the list. Risk identification Describe the perceived risks for each aspect listed in the template. What can go wrong? Why? See appendix 1 for examples of questions to ask. Use a new line for each separate risk. If there are no risks for a pre-defined trial aspect, record this as no risk. If the pre-defined aspect does not exist in the trial, record this as not applicable. Probability Score the probability that this risk will occur in this trial: 1=low 2=medium 3=high Impact Score the severity of the impact on patient safety and/or data validity if this risk occurs in this trial: 1=low 2=medium 3=high Risk score Add the score of Probability + Impact 2-3=mild 4=moderate 5-6=severe Risk mitigation level Choose one of three options how you will handle this risk. Accept: Limit: Avoid: You choose to accept this risk and will not take any measures to reduce the probability and/or impact. Suitable for mild risks. You choose to take measures to reduce the probability and/or impact of this risk to an acceptable level. The amount of risk reduction and the effort and cost you will spend on it, depends on the risk score. Suitable for any risk score. This risk is unacceptable and you will take measures to reduce the probability of this occurring to (almost) zero. This may include changing the intended design or procedures, and it may involve a substantial effort or cost. Suitable for severe risks. Table 2 - Risk mitigation Risk List all risks from table 1 for which the risk mitigation level was set to limit or avoid. Use a short description that links it to the longer description from the risk identification column in table 1. Risk mitigation strategy Describe the measure you will take to limit or avoid the risk. See appendix 2 for examples. Please note that any substantial changes to the trial design or trial procedures may introduce new risks or change the scores of risks, and may therefore require a revision of the risk assessment. Page 3 of 28
Table 1 - Risk assessment Trial aspect Risk identification Probability Impact Risk score Risk mitigation level Patient rights Informed Consent Privacy Safety Adverse Reactions Lack of efficacy Compliance to safety measures Safety reporting Safety management Protocol compliance Eligibility Treatment schedule Test procedures Data validity Timely data collection Adequate source documents Accurate CRF completion Reliable central data management Validity of results Power Blinding Sources of bias or variance Page 4 of 28
Trial aspect Risk identification Probability Impact Risk score Risk mitigation level GCP compliance Qualifications Resources Essential documents Page 5 of 28
Table 2 - Risk mitigation Risk Risk mitigation strategy Page 6 of 28
Appendix 1 Guidance for risk assessment Please note that this is only a guidance to help you think through the potential risks in a trial. It is an extensive list but it can never be complete. Trial aspect Patient rights Informed Consent Privacy Risk identification questions to ask Will patients be included requiring non-standard informed consent procedures, such as children or patients (temporarily) unable to give consent due to cognitive disorders? Is there limited time for patients to consider consent, due to urgency to start treatment? Are trial specific procedures needed to screen patients for eligibility, that would require pre-screening consent? Does the trial use multiple consent forms, such as pre-study ICF or separate PK sampling ICF? Does the ICF contain one or more optional items the patient should indicate yes-or-no consent for? Are there any aspects of the trial that are complex and perhaps difficult to understand for the average patient? Are there any unusual aspects in the informed consent process for this trial? Will any personal data be collected centrally, such as e-mail or address for distribution of patient questionnaires? Does the trial involve central collection of materials or documents that may contain patient personal data and need to be anonymized and coded by the site, such as CT images, lab reports, biological samples? Are there any additional expenses for the patient due to trial participation? Are there any other aspects in the trial that may pose a risk for upholding patient rights? Page 7 of 28
Trial aspect Safety Adverse Reactions Lack of efficacy Risk identification questions to ask Is there an increased risk of adverse reactions compared to standard care? Could there be an increased risk of unexpected adverse reactions compared to standard care? Is the trial intervention a licensed medicinal product or a standard procedure? If yes, to what extent is it used in a different way than in standard practice? How much is known about the expected adverse reactions in the context of the population and indication it is used for in the trial? If the investigational product is used in combination with other medications, how much is known about possible interactions? Does the trial require additional or more frequent test procedures(biopsies, scans etc) compared to standard care? Does this increase the risk of adverse reactions? Is there an increased risk of lack of efficacy of the treatment compared to standard care? Is the trial intervention a licensed medicinal product or a standard procedure? If yes, to what extent is it used in a different way than in standard practice? How much is known about the expected efficacy in the context of the population and indication it is used for in the trial? If the investigational product is used in combination with other medications, how much is known about possible interactions that may affect efficacy? Page 8 of 28
Trial aspect Compliance to safety measures Safety reporting Risk identification questions to ask Does the protocol have eligibility criteria for safety reasons that are different or more stringent compared to standard practice? Does the protocol require adherence to dosing instructions or dose modification rules for safety reasons, that is different or more stringent compared to standard practice? Does the protocol require additional or more frequent procedures (pregnancy test, blood chemistry test etc) for safety reasons, compared to standard practice? Do patients need to adhere to specific guidelines for safety reasons, such as storage or use of study drug at home, diet restrictions, use of contraceptives? Are there any specific safety measures in handling the study drug or study product for health care staff that they may be unfamiliar with or unaware of? Does the study drug or study product require specific storage conditions or preparation to warrant its quality, that is different or more stringent compared to standard practice, or that the site staff may be unfamiliar with or unaware of? Are there any other required safety measures that may be difficult to comply with? Are there any Adverse Events of special interest that require expedited (immediate) reporting by the site, even if they do not qualify as an SAE? Are there any safety data other than SAEs that need very timely reporting because they can influence decisions about the continuation of the trial? For example DLT information or AEs for the first treatment cycle in a trial with treatment cohorts. Does the trial require reporting of (S)AEs that are commonly exempt from reporting in trials from this sponsor? Such as progression of disease under study, nausea, CTCAE grade 1 AEs. Are there expected AEs for the trial population that qualify as SAE according to the protocol but may not be readily recognized as such by the investigators? Such as a short hospital admission due to neutropenic fever in leukemia patients. Are there any unusual or complex safety reporting procedures in the trial? Take into account if sites are participating that are unfamiliar with the sponsor s (S)AE reporting forms or procedures. What are the required timelines for reporting of AEs (AE CRF completion) to ensure that complete data are available for review of the overall safety of the trial? Is there a risk that these timelines will not be met? Page 9 of 28
Trial aspect Safety management Risk identification questions to ask Do the people involved in the collection, cleaning and assessment of safety data have sufficient knowledge of safety management procedures, the medical context of the trial and the investigational product? Are roles and responsibilities regarding safety management clear to all involved? Are there multiple parties and/or multiple countries involved in the trial with different requirements regarding the handling and reporting of safety information? Is there a risk that these requirements will not be met? Are the facilities and resources available to comply with regulatory safety reporting requirements? How will the sponsor keep track of the overall safety of the trial? If there is a safety concern that is only visible in aggregated data, such as an increase in frequency or severity of an AE above normal expectations, or a difference between the treatment arms, would you be able to detect it in time? Are there any unusual or complex safety management procedures in the trial? Is the trial blinded? Is there a clear and robust procedure regarding unblinding for SAE and SUSAR reporting? Are there any other aspects in the trial that may pose a risk for the safety of patients or the safety of people in the patient s surroundings or the safety of health care staff? Page 10 of 28
Trial aspect Protocol compliance Eligibility Treatment schedule Risk identification questions to ask Is there a risk that patients are enrolled that are in fact not eligible? Is there a risk that eligible patients are not enrolled because eligibility could not be confirmed in time? Does the protocol have eligibility criteria that are different or more stringent compared to standard practice? Does confirmation of eligibility require complex or time-consuming or unusual assessments? Is there a limit on the time passed between the date of an assessment and the date of enrolment to pass the eligibility criterion? For example WBC needs to be >1.0 x 109/l and assessment of WBC should be done no more than 7 days prior to enrolment. Does the protocol have eligibility criteria that are not defined by hard values but require medical judgment of the investigator? How difficult is this assessment for the investigators compared to standard practice? Is there any incentive for investigators to enroll patients that are not eligible? Either for their own benefit or for the assumed benefit of the patient, for example a lack of treatment options in standard practice? How different is the protocol treatment schedule from standard practice? A schedule that is very much like standard practice but has a few (important) changes, can pose a risk because the differences are overlooked and the usual routine is followed. A schedule that is very different and therefore unfamiliar, can pose other risks, specifically if it is complex. Are there many or complex decision points? Do decision points require a complex or unfamiliar assessment? Is there a risk that a decision is made based on an incorrect assessment or conclusion? For example a CR is required to continue to maintenance treatment and response needs to be assessed according to protocol criteria that are more stringent than standard practice. Page 11 of 28
Trial aspect Test procedures Risk identification questions to ask Does the protocol require additional or more frequent procedures (bone marrow smear, CT scan, etc) compared to standard practice? Does the protocol require complex or time-consuming or unusual assessments compared to standard practice? Does the assessment of any of the endpoints require central sample collection? Are any of the requirements for the collection (method, timing) or storage or handling or shipping of the samples complex or time-consuming or unusual? Are any assessments, that are essential for patient safety or validity of results, burdensome for the patient? Is there a risk of patient refusal? Are the sites compensated by the sponsor for the costs of additional assessments? Which specific protocol deviations would have a direct impact on patient safety or validity of the trial results? For example incorrect dosing in a dose finding trial. Does the protocol require additional patient visits compared to standard practice? This can mean more frequent visits or a longer continuation of follow up visits after the end of treatment. Are there any other aspects of the trial that may pose a risk for the adherence to the protocol? Page 12 of 28
Trial aspect Data validity Timely data collection Adequate source documents Accurate CRF completion Risk identification questions to ask Is there a risk that data are not collected within the required timelines? The required timelines are determined by scheduled (interim) analyses but also by the need to monitor the safety, protocol compliance and progress of the trial. Is the CRF extensive (many data) or complex? Are sites participating that are unfamiliar with the sponsor s data collection form design, e-crf system or procedures? Do data for a single patient need to be collected from multiple sources by the site (local data manager)? For example treatment in different hospitals or data generated by an off-site lab. Are source data for a single patient recorded in multiple locations or in multiple systems/files on site? Are all data sources known and available for the local data manager? Does the trial require to collect source data that are more extensive than standard practice? Are source data for a single patient generated at multiple locations? For example treatment in different hospitals or data generated by an off-site lab. Are source data for a single patient produced by multiple health care professionals? For example attending physicians, nurses, lab technicians. Are all persons involved in source data production sufficiently aware of the requirements for the trial? Is the CRF extensive (many data) or complex? Are sites participating that are unfamiliar with the sponsor s data collection form design, e-crf system or procedures? Are all data sources known and available for the local data manager? Do the people involved in CRF completion have sufficient knowledge of good data management practice and the medical context of the trial? Does the trial require collection of data that may be difficult to extract from the source data or that need interpretation of source data (medical judgment)? Is CRF completion adequately supervised and supported by the investigator(s) on site? Page 13 of 28
Trial aspect Reliable central data management Central data management: any storage and handling of data from the CRF to the dataset for statistical analysis, including data collection, data entry, data cleaning, data transfer or data extraction, data transformation Risk identification questions to ask Is there a risk of data corruption or loss of data due to a malfunction or calamity? Is there a risk of transcription errors or other inadvertent changes in the data in the process of data transfer from the CRF to the dataset as used for analysis of results? Is there a risk that data are intentionally modified without it being reported or detected? For example modifying response assessments in the database or in the dataset for analysis, without documentation that data were modified compared to the CRF. Is there a risk that over time or between patients data are not consistently collected or cleaned or assessed according to the same criteria? In blinded trials, is there a risk that the blind is inadvertently broken during the data management process? Do the people involved in the collection and cleaning of data have sufficient knowledge of data management procedures and the medical context of the trial? Do the people involved in managing the (digital) storage and transfer of data have sufficient knowledge of relevant data management procedures and do they have the relevant technical knowledge of the systems used? Are roles and responsibilities regarding data management clear to all involved? Are there any unusual or complex data management procedures in the trial? Are there any other aspects of the trial that may pose a risk for the validity of the data? Page 14 of 28
Trial aspect Validity of results Power Risk identification questions to ask Is there a risk that the target recruitment number needed for successful analysis of the trial is not sufficient? For example if dropout rate or event rate is not as expected. Is there a risk of not meeting the target recruitment or recruitment rate? Contributing factors can be: competing trials, insufficient compensation of costs, insufficient number of participating sites, slow activation of sites, high burden for patients, trial difficult to explain to patients, restrictive eligibility criteria. Is there a risk that too many patients are enrolled that are in fact not eligible? See eligibility for risk factors. Is there a risk that the blind is prematurely broken for too many patients? See blinding for risk factors. Is there a risk that too many patients have insufficient data to be evaluable for the study endpoints? You can make a distinction in the risk score for the primary endpoint and secondary endpoints. Is there a risk of premature withdrawal from treatment or loss to follow up of patients? Contributing factors can be: high burden for the patient from trial procedures or from additional hospital visits, inadequate management of expected adverse events, insufficient site awareness of the relevance of follow up information, trial participation does not match patient s expectations (informed consent process, patient information sheet). Is there a risk of non-compliance to the protocol resulting in missing data? See protocol compliance Is there a risk that the CRF design does not capture all the data required for analysis of the endpoints? Is there a risk that available data are not collected? See data validity? Page 15 of 28
Trial aspect Blinding Risk identification questions to ask Is there a risk, also in an open-label trial, that investigators are exposed to aggregate data or reports that may prematurely reveal (interim) results concerning the endpoints? Is there a risk that a patient requires emergency treatment by a physician not involved in the trial? Is there a risk that an investigator is unable to get an emergency unblinding for a patient? Are all involved site staff aware of the emergency unblinding procedure? Are instructions how to perform an emergency unblinding readily available at the site? Are all people involved in the emergency unblinding procedure aware of their responsibilities? Is the emergency unblinding procedure robust with regards to 24/7 availability of the service? Is the emergency unblinding procedure complex? Is there a risk that the blind is intentionally broken for a patient without it being reported or detected? Is there a risk that the blind is inadvertently broken? And is there a risk that this happens without it being reported or detected? Could a clinical event inadvertently break the blind? Page 16 of 28
Trial aspect Sources of bias or variance Risk identification questions to ask Which specific protocol deviations would be a potential cause of bias or too much variance in the data? See protocol compliance Specifically mind non-compliance regarding eligibility in trials where there is a multi-step process in treatment allocation and inclusion. For example registration for screening prior to enrolment, late randomization after enrolment, multiple randomizations. Is there a risk that over time or between patients data are not consistently collected or cleaned or assessed according to the same criteria? See reliable central data management Do the endpoints rely on hard values or do they require medical judgment? Is there a risk that the decision of the patient or investigator to prematurely withdraw from treatment is influenced by the randomization arm or by being exposed to interim results of the trial? Is there a risk of unbalanced randomization results? Is there a risk that investigators can influence or predict the randomization result? Is there a risk that a patient is randomized with an incorrect stratification factor? Is there a risk that this will occur multiple times? Is there a risk that the blind is broken for multiple patients without it being recorded? Also see blinding Are there any other aspects of the trial that may pose a risk for the validity of the results? Page 17 of 28
Trial aspect GCP compliance Qualifications Resources Essential documents Risk identification questions to ask Is there a risk that trial related tasks are performed by persons without adequate training or qualifications? Are there non-standard procedures in the trial that require additional training? Is there a risk that there is insufficient supervision of the quality of delegated tasks by the investigator? Is there a risk that the site does not have the required resources (time) or facilities for the trial? Is there a risk that essential documents are incomplete, absent or get lost? Specifically mind drug accountability records, delegation logs and signed informed consent forms. Are there any other aspects of the trial or the trial sites that may pose a risk for GCP compliance? Are there any other aspect of the trial that may pose a risk to patient safety or to the validity of the trial results? Page 18 of 28
Appendix 2 - Examples of risk mitigation strategies Please note that these are only examples. solutions or variations on the examples may be more suitable for your trial specific risks. Trial aspect at risk Informed Consent Privacy Adverse Reactions Lack of efficacy Possible risk mitigation strategies Robust design of IC documents and procedures, including peer review (PUC) and patient review of ICF. Training of site staff on ICF form and procedures. IC obtained by GCP trained investigators only. Review of site s IC process on-site (SEV) Collect and verify date of IC in enrolment database. Partial or complete review of trial specific signed ICFs on-site (trial specific monitoring visits). Robust design of systems and procedures used for collecting personal data, including testing of system security. Robust design of forms and procedures used for sample/materials collection. Training of site staff and/or central facility staff regarding coding procedures. Review of proper coding of materials received by central facility staff, followed up by trial team. Review of materials received at central facility by trial team or monitor ( audit ) Robust protocol design including safety measures and risk-benefit assessment, reviewed by EC and peer reviewed by writing committee, PUC. Review of safety data: annual safety reports reviewed by EC, interim analyses and DSMB review, continuous manual review of reported SAEs by PI. Note: requires timely and accurate data collection. Robust protocol design including risk-benefit assessment, reviewed by EC and peer reviewed by writing committee, PUC. Review of efficacy data: interim analyses and DSMB review. Note: requires timely and accurate data collection. Page 19 of 28
Trial aspect at risk Compliance to safety measures Possible risk mitigation strategies Robust protocol design regarding need and feasibility of safety measures and eligibility criteria, peer reviewed by writing committee, PUC. Review of adequate site facilities and/or site acceptance of protocol procedures, by site selection questionnaire and/or pre-study site visit, and/or review of information from SEV. Eligibility assessed by investigators only. Provide written instructions for patients, either in ICF or as separate document (NB EC approval). Provide written instructions for site staff (manual) regarding product handling. Training of site staff on patient safety measures and/or product handling. Review of site s general performance on protocol compliance on-site (SEV) Review of site s general process of eligibility assessment on-site (SEV) Review of site s general facilities and procedures on product handling on-site (SEV) Partial or complete review of trial specific protocol compliance, including eligibility, on-site (trial specific monitoring visits) Either scheduled or triggered (for cause visit) Partial or complete review of trial specific adherence to product handling instructions on-site (trial specific monitoring visits) Either scheduled or triggered (for cause visit) Partial or complete review of CRF data to verify protocol compliance, including eligibility, (remote monitoring) Note: requires timely and accurate data collection and implemented procedures for remote monitoring. Periodic or triggered (from data review) phone calls to site to review/request feedback on protocol compliance or product handling issues (remote monitoring) Partial or complete central collection and review of drug accountability records and/or patient diaries (remote monitoring, NB privacy) Collect and review data to verify eligibility prospectively in enrolment database. Page 20 of 28
Trial aspect at risk Safety reporting Possible risk mitigation strategies Robust protocol design regarding need and feasibility of safety reporting criteria, peer reviewed by writing committee, PUC. Robust design of safety data collection forms and reporting procedures, peer reviewed by PUC. Site staff involved in safety reporting is qualified by prior training and experience: general review of CV, delegation of tasks on-site during SEV. Alternatively, central collection and review of delegation log and CV copies. Alternatively, confirmation of prior good performance of sites as assessed by co-sponsor. Training of site staff on safety data collection forms and reporting procedures. Provide detailed safety CRF/report completion guidelines for site staff. Safety data requiring medical judgment assessed by investigators only (policy) Confirmation of safety data review by investigator (signature for CRF or final SAE report required) Periodic review and follow up of timely safety data collection (AE CRF, DLT CRF, SAE follow up) Review of collected safety data for discrepancies and/or signals of missed reports, internal (AE CRF discrepancy checks) or cross-check (AE-SAE, SAE-DLT, etc) Note: requires timely and accurate data collection and implemented procedures for remote monitoring. Review of site s relative performance compared to other sites on timely SAE reporting based on database review (annually in SEV) Review of site s general process of safety reporting on-site, including procedures for safety reporting if a patient is treated at multiple locations/sites (SEV) Partial or complete review of complete and accurate safety reporting on-site (trial specific monitoring visits with source data verification) Either scheduled or triggered (for cause visit) Note: optimal use of visits triggered by central review of data requires implemented procedures for remote monitoring. Page 21 of 28
Trial aspect at risk Safety management Possible risk mitigation strategies Robust safety management procedures, including trial specific procedures in blinded trials. Staff involved in safety management is qualified by prior training and experience. Trial specific training of staff involved in safety management in procedures, medical context, product information. Record and discuss delegation of tasks and responsibilities. Investigate, discuss and record trial specific safety management requirements. Safety cases requiring medical judgment, including SUSARs, reviewed by PI or (in blinded trial) independent medical reviewer. Review of safety data: annual safety reports reviewed by EC, interim analyses and DSMB review, continuous manual review of reported SAEs by PI. Note: requires timely and accurate data collection. Periodic review of safety database by safety desk coordinator for compliance to sponsor safety assessment procedures and SUSAR reporting timelines. Page 22 of 28
Trial aspect at risk Protocol compliance in general (including eligibility, treatment schedule, test procedures) Eligibility compliance Possible risk mitigation strategies Robust protocol design regarding need and feasibility of eligibility criteria, treatment schedule and test procedures, peer reviewed by writing committee, PUC. Robust design of IC documents, including peer review (PUC) and patient review of ICF, to ensure that patient knows what to expect, improve patient compliance and reduce premature withdrawal. Review of adequate site facilities for protocol procedures and/or site acceptance of protocol procedures including acceptance of available reimbursement of additional costs, by site selection questionnaire and/or prestudy site visit, and/or review of information from SEV. Training of site staff on critical protocol procedures. Assessments/decisions requiring medical judgment made by investigators only (policy) Review of site s general performance on protocol compliance, on-site (SEV) Review of site s general process of making trial related decisions, on-site (SEV) Partial or complete review of trial specific protocol compliance on-site (trial specific monitoring visits with source data verification) Either scheduled or triggered (for cause visit) Note: optimal use of visits triggered by central review of data requires implemented procedures for remote monitoring. Review of CRF data to detect recurrent issues with protocol compliance on site or trial level (remote monitoring) Note: requires timely and accurate data collection and cleaning and implemented procedures for remote monitoring. Periodic or triggered (from data review) phone calls to site to review/request feedback on protocol compliance issues (remote monitoring) Central review or central assessment of complex assessments (NB privacy), either prospective or retrospective. Eligibility assessed by investigators only. Review of site s general process of eligibility assessment on-site (SEV) Review of CRF data to verify eligibility for each patient (central data management) Note: requires timely and accurate data collection. Collect and review data to verify eligibility prospectively in enrolment database. Page 23 of 28
Trial aspect at risk Treatment schedule compliance Timely data collection Adequate source documents Possible risk mitigation strategies Partial or complete central collection and review of drug accountability records and/or patient diaries (remote monitoring, NB privacy) Periodic central review and follow up of timely data collection. (e-)crf and completion guidelines available prior to enrolment of first patient. Database and data management plan (procedures) available prior to enrolment of first patient. Review of adequate site resources for timely CRF completion and acceptance of CRF completion timelines, by site selection questionnaire and/or pre-study site visit, and/or review of information from SEV. Training of site staff on CRF completion timelines. Review of site s general process for CRF completion on-site, including communication lines between local data manager and clinical staff (SEV) Review of site s general quality of source documents on-site, including procedures for exchanging information if a patient is treated at multiple locations/sites (SEV) Training of investigators and other clinical staff. Provide templates for source document worksheets. Page 24 of 28
Trial aspect at risk Accurate CRF completion Possible risk mitigation strategies Robust design of CRF and reporting procedures, peer reviewed by PUC. Site staff involved in CRF completion is qualified by prior training and experience: general review of CV, delegation of tasks on-site during SEV. Alternatively, central collection and review of delegation log and CV copies. Alternatively, confirmation of prior good performance of sites as assessed by co-sponsor. Training of site staff on CRF completion and reporting procedures. Provide detailed CRF completion guidelines for site staff. Data requiring medical judgment assessed by investigators only (policy) Confirmation of CRF data review by investigator (signature for CRF required) Review of collected data for discrepancies (front-end edit checks in e-crf, queries, data cleaning). Review of site s general process for CRF completion on-site, including communication lines between local data manager and clinical staff (SEV) Partial or complete review of complete and accurate data reporting on-site (trial specific monitoring visits with source data verification) Either scheduled or triggered (for cause visit) Note: optimal use of visits triggered by central review of data requires implemented procedures for remote monitoring. Page 25 of 28
Trial aspect at risk Reliable central data management Power Possible risk mitigation strategies Robust procedure for database back-ups and restoring. Formal validation of database and data handling software. Functional test of trial database and discrepancy checks (no formal validation) Functional test of data handling software (no formal validation) Robust security settings for database access. Database audit trail. Data entry validation/review. Staff involved in central data management is qualified by prior training and experience. Trial specific central data managements procedures are recorded in data management plan and approved by statistician and PI, including procedures for maintaining the blind in a blinded trial. The data management plan is version controlled and implementation of changes recorded. Trial specific training of staff involved in central data management on data management plan and medical context of the trial. Record and discuss trial specific delegation of tasks and responsibilities. Mutual peer review of adherence to central data management procedures (trial specific and general) and good CDM practice by trial team, statisticians and PI. Data inconsistencies requiring medical judgment reviewed by PI. Review of enrolment database for recruitment rates. Periodic review of premature withdrawal rates (for example coinciding with annual progress report or DSMB review)note: requires timely and accurate data collection. Event rate monitoring by statistician. Note: requires timely and accurate data collection. Periodic or triggered (from data review) phone calls to site to review/request feedback on recruitment or premature withdrawal issues (remote monitoring) Page 26 of 28
Trial aspect at risk Blinding Bias and variance Possible risk mitigation strategies Robust data confidentiality procedures. Training of site staff in data confidentiality principles and procedures. Mutual peer review of adherence to data confidentiality policy. Robust (trial specific) procedures for maintaining the blind. Robust (trial specific) emergency unblinding procedure. Training of site staff on emergency unblinding procedure. Provide written instructions for emergency unblinding for site staff. Publish on publicly accessible part of HOVON website. Provide patient wallet cards with instructions in case of an emergency (phone number) NB EC approval. Periodically test availability of emergency unblinding service. Review of adherence to blinding and unblinding procedures and review of records on-site at the facility providing the service. Partial review to assess general process or complete review for all patients. NB review should not inadvertently break the blind. Robust randomization procedure. Review of CRF data to verify stratification factors for each patient (central data management) Note: requires timely and accurate data collection. Collect and review data to verify stratification prospectively in enrolment database. Page 27 of 28
Trial aspect at risk Qualifications Resources Essential documents Possible risk mitigation strategies General review of CV of all site staff (prior training and experience including GCP training) on-site during SEV and for echelon classification (NL only) General review of delegation of tasks and supervision by investigator on-site during SEV and for echelon classification (NL only) Central collection and review of delegation log and CV copies investigators CV only or also other site staff. Confirmation of site staff qualifications and prior good performance of sites as assessed by co-sponsor. Trial specific training of site staff. Trial specific review of site staff qualifications (CV and/or interview) and evidence of investigator supervision onsite (trial specific monitoring visits) Either scheduled or triggered (for cause visit) Note: optimal use of visits triggered by central review of data requires implemented procedures for remote monitoring. General review of availability of resources for trials during SEV and for echelon classification (NL only) Review of adequate site facilities and staff availability for protocol procedures and/or site acceptance of protocol procedures including acceptance of available reimbursement of additional costs, by site selection questionnaire and/or pre-study site visit, and/or review of information from SEV. Periodic or triggered (from data review) phone calls to site to review/request feedback on issues with available resources (remote monitoring) Review of site s general process and performance in maintaining essential trial documents, on-site (SEV) Central collection and review of (copies of) critical documents prior to site activation or in case of amendments (remote monitoring) Training of site staff. Provide site with self-assessment checklist of required essential documents, periodically and/or at the end of the trial. Trial specific review of essential documents availability on-site (trial specific monitoring visits) Either scheduled or triggered (for cause visit) Page 28 of 28