Risk Indicators and Thresholds

Risk Indicators and Thresholds are critical elements to the successful implementation of risk-based monitoring methodology into a clinical trial.

So, what is a Risk Indicator?

A Risk Indicator can be qualitative (for example: a site monitor’s assessment of site quality) or quantitative information that is used to monitor identified risk exposures over time, and are in many cases determined by comparing across programs, protocols, countries or sites, and are predominantly used at the patient level.

TransCelerate created a collection of Risk Indicators that it contemplates would be monitored Centrally or Off-site on an ongoing basis – which would allow for more rapid detection of possible issues to either further investigate or mitigate.

TransCelerate spotlights multiple Risk Indicator categories to help site personnel develop an optimal RBM plan:

Click on each puzzle piece to learn about the Risk Indicator categories

ISSUE MANAGEMENT means examining the outliers and trends in number or types of issues as well as concerns around number and severity of issues

ESSENTIAL DOCUMENTS focuses on the processing or storage of those documents critical to the trial

Regarding the INVESTIGATIONAL PRODUCT, monitoring plans should be focused on accountability, dosing, administration and compliance

SUBJECT RECRUITMENT refers to outliers in screen failure rate or enrollment rate, while subject discontinuation examines outliers and trends in ratio of subjects discontinued to subjects that are randomized, and the reason for discontinuation

DATA QUALITY quality looks at abnormal trends in data such as lack of variability, case report form (CRF) completion, adherence to data entry instructions, and proactive discrepancy management (for example, examining the number of queries, and query response time)

STAFFING, SUPPLIES & EQUIPMENT, with a particular focus on amount of staff turnover and staff training needs, delegation of responsibilities, and adequacy, maintenance, calibration and storage of supplies and equipment

ON-SITE WORKLOAD BASED TRIGGERS refers to the amount of data pending SDV or other monitoring activities that are conducted on-site

SAFETY refers to the suspected unexpected serious adverse reactions – concerns regarding processing of safety information, non-serious adverse events (AEs) and serious adverse events (SAEs)

TransCelerate conducted a blinded survey in the fourth quarter of 2014 on Risk Indicators and associated benefits, which informed a Risk Indicator Library composed of more than 140 Risk Indicators. From this library, clinical trial sponsors can choose and adjust Risk Indicators specific to the above categories, and apply them to their clinical studies.

As technologies and methodologies evolve, new Risk Indicators will be identified in accordance with those advancements. Moreover, as the RBM model becomes more commonplace, the potential to test new Risk Indicators and determine their utility compared to established Risk Indicators will grow.

How do Thresholds play into this?

Thresholds are the level, point, or value associated with a Risk Indicator that will trigger an action. Thresholds can aid in decision making, data quality and GCP compliance.

Actions after a Threshold is reached:

When a given Threshold is reached, a decision needs to be made regarding the appropriate action to take. The choice could be as simple as continuing Centralized or Off-site monitoring for potential trends. If the event is more serious, immediate investigation may be warranted. Actions are predominantly on the site level, and not on the trial level. Examples of actions for Thresholds include:

• Assessing other types of data remotely
• Contacting the site to gather additional information
• Visiting the site to assess documentation only available on-site that cannot be made available remotely

Once it is determined, via the Threshold, that a risk requires some form of mitigation, a decision should be made as to whether the solution may be accomplished remotely or require an On-site visit. If possible a remote mitigation is preferable because it can be done right away, as opposed to waiting for an On-site visit to resolve. The sooner it is addressed, the higher chance of preventing recurrence.