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May 27, 2014

Work smarter, not harder in clinical trials: risk-based monitoring (RBM)

There is a lot of interest in risk-based monitoring (RBM) of clinical trials, and it’s easy to understand why. Monitoring activities can account for 25-30% of the cost of a clinical trial, so any efficiencies to be gained can come at substantial savings for the trial sponsor. ICH Guideline E6 states that the “sponsor should ensure trials are adequately monitored.”

But why are clinical trials monitored in the first place? There are several reasons: to ensure that clinicians are carrying out the trial according to the protocol, that the data has limited errors and is of high-quality for analysis, and above all else, to protect the well-being of the clinical trial participants.

Traditional interpretation of the ICH Guidance has often led to 100% source data verification (SDV) of respective case report forms through onsite monitoring. Such monitoring activities can also identify deficiencies in site training and uncover fraudulent behavior.  However, such extensive onsite review has several drawbacks:

  • Expensive (Eisenstein et al., 2005; Funning et al., 2009; Tantsyura et al., 2010)
  • Time-consuming, with effort spent on data of little importance to the goals of the trial
  • Error prone  (Tantsyura et al., 2010)
  • Limited in scope (difficult to compare data across pages, participants and sites)
  • In contrast, RBM makes use of central computerized review of clinical trial data and site metrics to determine if sites should receive more extensive quality review through on-site monitoring visits.

    How important is this topic? There are numerous regulatory guidance documents addressing this issue: the US Food and Drug Administration, the European Medicines Agency and the Medicines and Healthcare Products Regulatory Agency of Great Britain. Further, there are recent publications on the topic from TransCelerate Biopharma, a consortium of pharmaceutical and biotechnology companies, as well as the Clinical Trials Transformation Initiative, a public-private partnership comprised of more than 60 organizations.

    We have heard the call. Recently-released JMP Clinical 4.1 has incorporated several tools to help identify potentially fraudulent activities within a clinical trial, and we are currently in the active development of an RBM platform to monitor ongoing studies for Version 5.0 (Figure 1). These tools will be extremely flexible, allowing users to take advantage of their CDISC-formatted data and other available site-metrics, and define and vary risk thresholds that are appropriate to the current trial. All of this power and flexibility is contained within the visually striking and interactive framework expected from JMP Clinical.

    Figure 1. Risk-Based Monitoring Views of JMP Clinical

    Over the next several weeks, we’ll highlight the features that will help your organization work more efficiently, and show how integration with past JMP Clinical features such as Patient Profiles and Adverse Event Narratives, and recent features for Fraud Detection and Snapshot Comparisons will accelerate trial reviews and manage safety and quality risks.

    Community Member

    Dr. Ben Locwin wrote:

    I agree fully here. Use of RBM is similar to using Bayesian statistics to find the submarine USS Scorpion (also used for other means frequently as part of the creatively-named "Bayesian Search Theory"). The Air France flight data recorder was similarly found in 2009. A 100% review of the raw data isn't needed, just - as the title suggests - a smarter review of the data, and 100% in the cases where it is necessary. With RBM, we're essentially pre-specifying the priors based on each site's relative risk.

    I have provided oversight for many clinical trials, and issues such as these really do drain an incredible amount of resource and energy.

    Community Member

    Rhonda Roberts wrote:

    Is the plan for JMP Clinical 5.0 to only use data in CDISC format? This would be an extremely useful tool-but restrictive if that is the case. Thanks

    Richard Zink wrote:

    Yes, JMP Clinical will take advantage of data that is part of the CDISC study database. It will also be possible to enter data that does not conform to CDISC and incorporate these variables into risk calculations. Stay tuned.