New FDA Thinking On Risk-Based Monitoring
By Marc Buyse, ScD, Founder, CluePoints Inc.
In August the U.S. Food and Drug Administration (FDA) published its much anticipated current thinking on clinical trial oversight and the development of risk-based monitoring (RBM) strategies. Since the release of its draft guidance on the topic in 2011, the agency has helped fuel growing consensus across the industry that centralized RBM techniques could better assist sponsors in meeting their regulatory obligations, while enabling clinical trials to be more safely, quickly and economically executed. Providing relief from the resource heavy process of full on-site monitoring, which is notoriously fraught with accuracy and effectiveness issues, sponsors are likely to find that harnessing these alternative monitoring strategies is a relatively simple process.
FDA Guidance for Industry
The FDA's Guidance has been developed to assist sponsors of clinical investigations in developing RBM strategies and plans for investigational studies of biopharmaceuticals and medical devices. Its aim is to enhance human subject protection and the quality of clinical trial data by focusing sponsor oversight on the most vital aspects of study conduct and reporting.1Over the past two decades, the number and complexity of clinical trials has grown significantly, while studies have become more geographically dispersed as a result of outsourcing trends. At the same time the rate of drug approvals has declined steadily, while the cost of clinical research continues to rise. In the midst of these challenges, traditional site monitoring stands out as a significant expense for sponsors accounting for 30% of overall costs in global clinical trials, but resulting in less than 3% of any data changes.2 A highly time-consuming activity that cannot be shown to adequately ensure the integrity of the research process2, traditional site monitoring demands hundreds of man hours that in the current climate sponsors simply cannot afford.
In light of these issues, the FDA suggests that regular on-site monitoring every four to eight weeks with 100% Source Data Verification (SDV) is no longer called for in modern research, particularly due to the technological advances that make it possible to monitor data quality more efficiently. The agency proposes that the use of a centralized, risk-based approach can reduce the cost of site monitoring, with the ultimate goal of enhancing the protection of human subjects. It is now stated that certain data anomalies such as fraud, fabrication of data and other non-random data distribution may be more readily detected using risk-based strategies, and as a result overall quality of data can be improved.
Practical Execution of RBM
The FDA guidance is clear that no single approach to monitoring will be appropriate for all studies. As such, it is recommended that a unique monitoring plan is designed for every trial that is tailored to the specific human subject protection and data quality risks associated with that study. For example, a trial involving innocuous procedures or well-known treatment could involve far less monitoring than a trial involving invasive procedures or experimental drugs. It is recommended that a monitoring plan only be developed once the particular risks associated with a study have been assessed, and that data be analyzed on an ongoing basis to review and adapt the monitoring strategy.1The monitoring plan should document the various methods that will be used and the rationale behind their use, with a focus on preventing important and likely sources of error in the conduct, collection and reporting of critical data. Sponsors need to prospectively identify critical data and processes necessary for trial integrity, before performing a risk assessment to identify the risks that could impact the collection of data or the performance of processes.1 At this point, a plan can be developed that focuses on the important and likely risks to critical data and processes.
These new recommendations are critical as the industry faces continuing challenges to ensure quality clinical trials with fewer resources and reduced costs. The document highlights the fact that sponsors should be focusing or 'targeting' their on-site monitoring activities with one of the most common ways of doing this being remote monitoring. This involves taking a look at the data off site and determining where issues may be prevalent. The FDA has listed several techniques that may be considered by sponsors and reflect a modern RBM approach, focusing on critical study parameters and relying on a combination of monitoring activities to oversee a study effectively. One such method is the use of statistical techniques in the form of Central Statistical Monitoring (CSM).
Central Statistical Monitoring
CSM looks at all the variables and endpoints that are patient-related, determining the expected values of each variable by assessing and examining the data from all sites in order to identify statistical outliers. Using statistical methods, signals can be detected to better manage risk and determine variations from one site to another, and the difference between expected and observed data in each site. This allows sites which are outliers to be identified and resources to be deployed as necessary to improve data quality.
The technique uses complex algorithms to drill down into individual patient data to detect issues that could jeopardize a study and create a road block to successful regulatory submission. This agnostic approach is based only on the actual clinical data and not on subjective indicators. The idea behind this is that all variables are indicative of quality, whether it be lab data, clinical data, baseline data or treatment outcomes, everything is analyzed and deemed to be important. In a clinical trial, everything that is collected should be worth collecting, and therefore worth checking, CSM ensures the ability to determine the quality of the data and ensure that monitoring efforts focus on errant sites immediately.
When using CSM during a study, sponsors can take corrective action in a timely manner to prevent issues becoming deep-rooted and re-analyze data regularly as part of an iterative process. The sponsor can perform focused site monitoring visits, identify CRA and site retraining needs, or develop site tools to provide clarification on protocol and study processes. The protocol is implemented in the same manner in all sites involved in a study using the same CRF, and the approach requires minimal work for the study team in gaining objective information in order to optimize on-site monitoring by targeting centers at risk. An additional benefit of CSM is that for sponsors who strategically outsource to CROs, the method can be use as an effective oversight tool to regularly check the quality of data. The solution is therefore proving vital in informing the selection of CRO partners and investigative sites for future trials.
Conclusion
The new FDA recommendations represent a major step forward for the industry and one that all sponsors should embrace. The opportunity to improve data quality while mitigating risk is the outcome that all sponsors are looking for and the FDA is encouraging an approach that not only does this, but offers companies means to increase efficiencies and, ultimately, reduce costs. In light of new recommendations, statistical monitoring methods are proving critical when large volumes of data are involved because the reviewing of all this data manually can easily introduce error. By implementing these techniques sponsors can reduce the costs of clinical trials while making better use of resources and improving study success rates.
To learn more about CluePoints solutions, please visit www.cluepoints.com
References
1. U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for Industry: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring. Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM269919.pdf (accessed 30 August 2013).
2. Califf, RM. ACS and Acute Heart Failure Models. Speaker presentation at the Institute of Medicine Workshop on Transforming Clinical Research in the United States, October 7–8, 2009, Washington DC. Available at http://www.iom.edu/Reports/2010/Transforming-Clinical-Research-in-the-United-States.aspx (accessed 30 August 2013).