COO’s Blog

Removing resistance to RBM one protocol risk assessment at a time …


Jan 6th 2019:  In the last weeks of December I was heavily involved in facilitating protocol risk assessments for two very different prospects.  The first was a phase 1 paediatric study, where the risk assessment is being led by the sponsor and being initiated at the point of protocol synopsis.  The second was a phase II oncology study where the risk assessment is being led by the CRO partner and the study is just about to begin site initiations.


During the kick off for the phase 1 paediatric study, the process was met with open hostility from the clinical science function, but very much supported from the operations, project management and safety functions.  After setting out the process and guiding the team through some fascinating discussions where the clinical science function was very much at the centre, we wrapped up the meeting with a solid list of critical variables, good set of risks and excellent mitigating actions which included agreed changes and clarifications to the protocol, and an agreement to seek further expert guidance from the PK consultant.  On the surface this study seemed to be following standard of care processes, although dealing with a vulnerable population.  But when we started to work through the processes we were asking the site to perform, and the data being collected, the complexities became evident very quickly.  In spite of that the team came up with some excellent controls that could be put in place to simplify the processes, support the sites and set the study up for the best chance of success and generating good quality data.  We even received public acknowledgement from the clinical science function that it was a very worthwhile exercise and there were lots of notes to follow up on with the protocol.  A great result!  I left the meeting with a grin on my face and a spring in my step … A win for process and a win for the risk based approach!  I look forward to seeing how this team implements their study conduct risk controls.


In contrast to the first, the second risk assessment process was met with great enthusiasm. It’s the team’s first foray into the world of risk based monitoring and there was genuine excitement to be spending time discussing the study and how to approach the study conduct phase.  What I was really encouraged by was that there was cross functional representation.  The CRO provided medical input into the process and that was the focus, not the usual operational delivery metrics, such as first patient in, recruitment etc.  While there were some risks raised around patient population, the team did a great job in defining the critical variables and working methodically through the risks to those variables, focusing on subject well-being, ethical considerations and data quality. Items such as: the importance of treating emergent AEs; the impact on earliest date of clinical disease progression if AEs were not assessed and recorded accurately; impact of including subjects with poor life expectancy; and the complexities of DLTs, drug interruption and dose reductions.  The other fascinating point was that when it came to evaluating the detection of risk, the general assessment was that the risk would be easily identifiable by onsite monitoring.  However, when we started to pick into this, it became apparent that detecting this risk was reliant on all monitors picking up on all nuances without any room for error, and that if it was caught during monitoring, it would be patient by patient.  The implication of that is that by the time the monitor realised there was a trend, it could be too late.  During these discussions, the power of centralized data monitoring, looking at data per site and subject became obvious.  The team were able to see how KRIs, specifically designed to control the study risks, could be used as part of their monitoring strategy, together with targeted onsite monitoring.  The team were strong advocates of onsite monitoring, with targeted activities from the central monitoring, because the onsite monitoring supported the investment in the site relationship.  This is an integral and important part of their risk controls, together with the oversight of some of the processes which were going to be difficult to assess remotely for this study, such as drug accountability and supply management.  All very sound justification!


Being hands on with the study teams is such a valuable activity for me, it helps me to better understand the resistance points, how to demonstrate the importance of protocol risk assessment and the power of centralized monitoring to in early identification of errors and trends.  Hopefully this helps the organizations we work with to embrace new ways of working and realise the efficacy of these processes …  and it helps me bring back real world experience to our product development team.


RBM is not about reduced SDV, that may be one of many outcomes, but it’s not the intent or benefit of the process.  And no study is too small to apply a risk based approach, just consider the positive impact to our phase 1, 24 patient study …