Myeloma UK Clinical Trial Network (CTN) Aims Efficiently deliver a portfolio of early phase trials Allow patients to access novel treatments Reflect UK clinical practice Enable a transition from phase I → phase II → phase III Current portfolio 3 trials open 3 trials closed to recruitment 3 trials in set-up/design 2 trials completed Who we are – coordinating centre for MUK CTN. Aims of the network are:… We have an expanding team and a steady stream of trial...

Previous monitoring strategy Risk assessment performed at the beginning of the trial Monitoring plan written – pre-determined number of site visits More patients = more site visits Major issues eg Serious Breach = a site visit Risk assessment carried out during set-up looked at patient safety and data quality risks as well as other issues such as IMP logistics and potential impediments to recruitment. The central and site monitoring covered by the monitoring plan was mainly concerned with ensuring patient safety and data integrity and dictated a certain number of visits per site. There were really only a couple of triggers for additional visits - a high number of patients at a site or major issues namely a serious breach. However, as the trials we manage are all phase I and phase II, and therefore inherently higher risk than later phase trials, site visits and thorough in-house data checking are always necessary. Restrictions of previous strategy: - Common issues such as protocol violation and CRF compliance/quality were not consistently monitored and taken into account for monitoring Information sharing between TM/DM and monitoring staff was limited

Risk-based monitoring Inspiration MRC/DH/MHRA Joint Project - ‘Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products’ CRUK Drug Development Office - Risk Assessment Tool How to implement in the Myeloma UK trials? Risk-based approaches to trial management and monitoring are not new. When we decided to update our monitoring strategy for the Myeloma UK trials, we were taking inspiration from a few sources, including the….. And the risk assessment tool developed, and generously shared by, the CRUK drug development office. However, we found that this tool didn’t quite fit our portfolio so we had to work out how best to implement a similar approach that worked for us. :

Implementation Which parameters do we want to monitor? What issues occur on our trials? What data do we already collect that could be utilised? What new data do we need to collect? What will we do with the information generated? Who will keep the tool updated? The questions we asked ourselves were: We decided to carry

Our risk-based monitoring tool   Low (1) Medium (2) High (4) Number of protocol violations no violations 1 violation 2 or more violations Number of Serious breaches no serious breaches - serious breach occurred Other issues on monitoring log no issues 1-3 issues more than 3 issues CRF compliance % 90% or higher 70-90% less than 70% Average days to return data less than 3 days 3-10 days more than 10 days SAE reporting within timelines 1 SAE outside of timelines multiple SAEs outside timelines Total data queries out >10 data queries out 10-30 data queries out > 30 data queries out Key personnel change no changes to key personnel changes to Lead Research Nurse or other key team member in the last 6 months change to PI in past 6 months, or high staff turnover in past 6 months Recruitment % vs plan recruitment >80% of plan recruitment 80-110% of plan recruitment greater than 110% of plan Site visit/SDV outcome - data No issues/no visit Some issues seen Serious issues seen Site outcome- pharmacy Before the trial starts, we will score the risk of the trial based on a number of factors such as the novelty of the IMPs involved, known clinical safety issues, complexity of the protocol and patient population – I won’t show an example of this here. This is used to inform the monitoring plan ie the standard number of site visits and level of central montoring required. We have then developed a tool to allow us to assess the performance of sites on an ongoing basis throughout the life of the trial, looking at a number of parameters and allowing us to allocate a score depending on whether they fall into the low, medium or high risk category. The parameters that we look at are shown here: Briefly describe parameters used to assess sites monthly.

Our risk-based monitoring tool We then have a monthly snapshot comparing all sites and highlighting key issues and this is useful at meetings.

Our risk-based monitoring tool Site data updated monthly by trial coordinator Monitor adds information from site visits Used by all members of team Used to help decide when additional ‘targeted’ or ‘triggered’ visits are required How this works in practice…. As time goes on and we have more experience with the tool we may be able to set specific thresholds to determine when extra visits are required but we are currently using the objective measures in the tool combined with a certain degree of subjectivity to determine when what we call targeted and triggered visits are required. Targeted visits are like a first warning and triggered visits are the next step up – triggered visits are notified to the sponsor and would be carried in response to individual serious incidents or perhaps repeated violations despite a previous targeted visit and remedial action being put in place. I think the tool will like always be used with some subjectivity and that flexibility is necessary to allow us to act as we think appropriate, as long as this is clearly justified. In the future, hope that a similar approach will be adopted by other teams at the CTRU.