Writing an Integrated Quality and Risk Management Plan (IQRMP) involves identifying risk factors and developing a contingency plan to manage the risks that cannot be eliminated. Risk factors can be monitored using Key Risk Indicators (KRI) which are metrics calculated from the collected data associated with risk factors. For instance, most studies consider the AE rate a risk factor and will monitor it on a periodic basis by calculating the site-specific number of adverse events divided by the number of subject-days. A risk signal is typically triggered when a Key Risk Indicator (KRI) metric’s value falls beyond its set limits and a contingency plan includes specific actions to be deployed when risk signals are triggered. Nevertheless, because the contingency actions are planned early in the risk management process, they may lack the context in which the risk signal is encountered sometime later. Thus, when a risk signals are eventually triggered, the actions that have been planned for may not be the most appropriate ones anymore. In fact, a risk signal can be triggered by a number of possible situations that are not always easy to envision and planned contingency actions may not appropriately address a risk when it is encountered in reality. For example:
- A high Missed Dose Rate may occur because a subject has not been trained properly regarding treatment administration or the site has not distributed enough doses to the subject. Therefore contingency actions may include providing additional training to the subject or verifying the drug distribution process at the clinical site. Nevertheless, when a Missed Dose Rate signal is triggered in reality, analysis of the signal may reveal that a subject decided to stop taking the medication and withdrew from the study at its next visit to the site. Retraining the subject would be unethical in this case. Verifying the drug distribution process would also do nothing to contain the detected risk. More appropriate measure would be to document in a formal centralized monitoring report the fact that the subject stopped taking the medication and simply chose to withdraw from the study for whatever reason. Information related to this elevated KRI metric can then be taken into account when evaluating this site-specific KRI at the next centralized monitoring review. Rethinking the calculation of Missed Dose Rate by adding some IF-THENs in the algorithm may be another solution but this option should be considered carefully as modifying calculations may also cause unforeseeable consequences.
- A high Query Rate and Error Rate may occur because the data entry person is not well trained. Therefore the planned contingency actions may include re-training the data entry person or increasing the required %SDV to make sure that all the errors that are made are caught by the on-site monitor. Nevertheless, when a high Query Rate signal is triggered in reality, analysis of the signal may reveal that the error is actually the result of the EDC system design. For example, a drug accountability form might need be saved before all drug distribution information is available, therefore generating queries because the EDC system detect missing information and errors are generated because entries are being made after initial entries into the form. Retraining the site or increasing SDV will do little to contain risk in this case. More efficient contingency action might involve modifying the CRF completion guidelines, inactivating the automatic queries in the EDC system or rethinking the calculation of the KRI metrics so that the drug accountability CRF is not taken into account in the calculation of query and error rates.
Many situations are hard to foresee before they are encountered and planning for all possibilities goes against the spirit of Risk-Based Monitoring (RBM). Indeed, RBM implies concentrating on what is important and using resources efficiently. Nevertheless, the value of planning is never wasted. Indeed, planning for risk contingency early provides perspectives that serve to adopt optimal processes, systems and people. As unforeseeable situations are encountered, they become less unforeseeable. We learn from experience and central monitoring processes must be able to register lessons learned and be continuously improved upon. Indeed, KRI calculations can be fine-tuned to dampen the noise and the planned contingency actions can be modified to take into account the most current information.
The take-away point is that central monitors should plan for risk contingency actions but be ready to investigate and adapt their remedial actions at the time risk signals are triggered. They should also use flexible tools that allows them to quickly make changes to the KRI’s calculations. Furthermore, they should employ a reporting format that allows them to document the context in which risk signals are encountered and the rational for the changes made to their central monitoring approach. In centralized monitoring as in life, change is the only constant.