Susan Wiskow, Senior Clinical Project Manager
Since the release of ICH’s Guidance for Industry, Integrated Addendum to ICH E6(R1): Good Clinical Practice E6(R2) recommending the use of a risk-based approach in quality management systems, including clinical trial monitoring, I’ve observed some common misconceptions. The following five misconceptions could actually lead to increased risks for your clinical trials, if not properly addressed.
1. Risk management planning is only important if you plan to use Risk Based Monitoring (RBM).
If you say in your protocol that you will adhere to ICH GCP, you need to understand that the GCP revisions encompass quality management processes and assessments that must be done, regardless of whether or not you plan to use risk based monitoring.
- Identify risks to critical study processes and data during protocol development, evaluate and control risks, focus on continual improvement throughout the clinical trial, conduct periodic review of risk control measures, and report important deviations from the predefined quality tolerance limits.
- Ensure processes are in place to cover: database system setup, installation and use, system validation, functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning and decommissioning. The responsibilities of the sponsor, investigator and other parties with respect to the use of these computerized systems should be clear, documented and the users should be provided with training in the use of the systems.
- Put a CAPA system in place. Regardless of the type of monitoring being performed, ensure there is an effective process so that when significant noncompliance is discovered, you can perform a root cause analysis and implement appropriate corrective and preventive actions.
2. Risk Based Monitoring is cheap.
While there are cost savings associated with reduced monitoring travel expenses and fewer visits, on-site visits will still need to occur when risk thresholds are triggered and more project oversight and data management time is required upfront and throughout the trial.
At the time of protocol development, identify and evaluate risks which have the potential to impact subject safety and welfare or data integrity. For each risk, consider the likelihood of occurrence, the impact should it occur, and the extent to which errors would be detectable. Identify risks which should be mitigated by activities, and define the triggers and related actions in your monitoring plan, such as increasing the level of monitoring at a site upon discovery of one unreported serious adverse event.
3. Risk Based Monitoring means you’ll never need to monitor onsite again.
GCP suggests that a combination of on-site and centralized monitoring activities may be appropriate, not that on-site visits should be eliminated. And while the extent and/or frequency of on-site monitoring may be reduced, some activities are difficult or impossible to complete remotely, such as review of original signed Informed Consent Forms, and review of investigational products and associated storage requirements at the site, etc. Also, some sites cannot or may not be willing to provide remote access to source documents.
At the time of site identification and qualification, discuss technological capabilities and the site’s comfort level with providing remote access to medical records. Document any requirements needed, such as required training for the monitor prior to receiving access. Define what monitoring activities can be conducted remotely versus which activities must be done on-site, within your monitoring plan.
4. Risk Based Monitoring is significantly less work.
Centralized monitoring methods, while improving data quality, are time intensive and per GCP include (a) Routine review of submitted data. (b) Identification of missing data, inconsistent data, data outliers, unexpected lack of variability and protocol deviations.
These issues may be indicative of systematic or significant errors in data collection and reporting at a site or across sites, or may be indicative of potential data manipulation or data integrity problems.
- Use statistical analyses to identify data trends such as the range and consistency of data within and across sites.
- Analyze site performance metrics.
- Define methods for centralized data review and targeted on-site monitoring within your Monitoring Plan.
5. If you choose NOT to use Risk Based Monitoring, and opt for 100% source data review, you don’t need to do any Centralized monitoring.
Centralized monitoring is a remote evaluation of ongoing and/or cumulative data collected from trial sites, performed in a timely manner. This activity is important to protect data integrity and complements traditional monitoring, because it can help to identify trends, data outliers, and even identify potential fraud not as easily identified when reviewing individual sites.
Regardless of what monitoring method(s) you plan to use for your study, thoughtfully consider how you will identify and address trends, data outliers, and potential fraud. For example, such one site has data that is “too perfect”, such as a 5 year study with no out of window visits or subject weights that never change from visit to visit.
In my experience, managing multiple clinical projects in many different therapies, the best approaches to managing risk involve thoughtful planning that starts with your quality system and includes developing a risk management strategy, focused on the primary objectives and risks associated with your trial.
If you have questions about managing risk in clinical trials, RCRI has qualified resources that can help you. Contact Samantha Thrun at firstname.lastname@example.org or 952-224-2260 to be put in touch with an RCRI expert.
ICH Harmonized Guideline Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E(R2)