Year : 2013 | Volume
: 4 | Issue : 4 | Page : 193--195
Taking the 'Risk' out of risk-based monitoring
Head-Medical Affairs, Novartis Health Care Private Limited, Division of Pharmaceuticals, Worli, Mumbai, Maharashtra, India
Head-Medical Affairs, Pharmaceuticals Division, Novartis Health Care Private Limited, Sandoz House, Worli, Mumbai, Maharashtra
|How to cite this article:|
Gupta A. Taking the 'Risk' out of risk-based monitoring.Perspect Clin Res 2013;4:193-195
|How to cite this URL:|
Gupta A. Taking the 'Risk' out of risk-based monitoring. Perspect Clin Res [serial online] 2013 [cited 2020 Feb 21 ];4:193-195
Available from: http://www.picronline.org/text.asp?2013/4/4/193/120165
Clinical site monitoring accounts for approximately 30% of the total cost of a clinical trial. Monitoring has always been considered as an important aspect of clinical trial and has been ingrained in every sponsor and contract research organization (CRO) as the security blanket allowing them to feel secure in the integrity of the study processes and data. ICH E6 defines monitoring as: "The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s)".  Traditionally to ensure patient safety and data integrity has been interpreted by the industry as requiring 100% source document verification (SDV) and to monitor the site every 4-6 weeks. This process is slow, costly, and ineffective. Monitoring the site by physically being present at the site is expensive both in terms of money spent on logistics as well as time spent by numerous Clinical Research Associates across all sites. Much more time is spent on activities that could have easily been done from a remote location. It is reported that almost 46% of on-site monitoring effort goes into SDV (Source Data Verification), which translates to about 34% of the total phase III study budget. 
With fewer resources available, we are continually being required to "do more with less". Thus, the concept of centralized monitoring is introduced, which is a remote evaluation carried out by sponsor personnel or representatives (e.g., clinical monitors, data management personnel, or statisticians) at a location other than the sites at which the clinical investigation is being conducted. Adopting risk-based monitoring (RBM), industry shall become more effective in using what is, in effect, a diminishing resource.
The basic concept of RBM is to focus attention on the data, documents, and processes, which are critical and important. There could be different scenarios at different sites or at the same site based on study progress. RBM approach focuses on the high risk data points (data points that are prone to mistakes or difference in interpretation or transcription and which have a high impact on quality of the data and the outcome of the study).
It is not a "nice to have"; It is essential, because the regulators are now telling us that we have to do RBM. Food and Drug Administration (FDAs) recent 2013 guidance regarding monitoring practices encourages sponsors to consider a change in approach to monitoring. FDA believes that RBM could improve sponsor oversight of clinical investigations. A risk-based approach to monitoring does not suggest any less vigilance in oversight of clinical investigations. Rather, it focuses sponsor oversight activities on preventing or mitigating important and likely risks to data quality and to processes critical to human subject protection and trial integrity. This guidance is therefore intended to make it clear that RBM, including the appropriate use of centralized monitoring and reliance on technological advances (e.g., e-mail, webcasts, online training modules) can meet statutory and regulatory requirements under appropriate circumstances. FDA encourages greater use of centralized monitoring practices, where appropriate, than has been the case historically, with correspondingly less emphasis on on-site monitoring. No single approach to monitoring is appropriate or necessary for every clinical trial. FDA recommends that each sponsor design a monitoring plan that is tailored to the specific human subject protection and data integrity risks of the trial. Such a risk-based plan would include a mix of centralized and on-site monitoring practices. Monitoring activities should focus on preventing or mitigating important and likely sources of error in the conduct, collection, and reporting of critical data and processes necessary for human subject protection and trial integrity. This guidance discusses the risk assessment, a component of risk management, as applied in the context of clinical monitoring. Risk assessment generally involves identifying risks, analyzing risks, and then determining whether risks need to be modified by implementing controls (e.g., processes, policies, or practices). Sponsors should perform a risk assessment to identify and understand the nature, sources, and potential causes of risks that could affect the collection of critical data or the performance of critical processes. The identified risks should be assessed and prioritized by considering the following:
The likelihood of errors occurringThe impact of such errors on human subject protection and trial integrityThe extent to which such errors would be detectable.Sponsors should use the results of the risk assessment in developing the monitoring plan. The type (e.g., on - site, centralized), frequency (e.g., early, for initial assessment and training versus throughout the study), and extent (e.g., comprehensive (100% data verification) versus targeted or random review of certain data (less than 100% data verification)) of monitoring activities will depend to some degree on a range of factors, considered during the risk assessment, including the following: Complexity of the study design, types of study endpoints, clinical complexity of the study population, geography, relative experience of the investigator and of the sponsor with the investigator, electronic data capture, relative safety of the investigational product, stage of the study, and quantity of data.  FDA guidance would impact the sponsors globally and in India in many ways; to cite a few, for example,
Adaptive on-site monitoring based on inputs from centralized monitoringEffective use of Electronic Data Capture for ongoing review of site performance and dataReal-time data management and statistical analysis during the trial conductExpeditious review and communication for anticipated actions for noncomplianceTraining of monitors/data management/statistics teamsParadigm shift in monitoring from quantity to quality.Organizations, which were earlier cautious about adopting RBM, are now actively discussing how to best implement RBM instead of whether to, after the release of regulatory guidance.
Initial monitoring intensity (amount, frequency and location) should reflect the overall risk of the study. Observation and judgment can identify trends, anomalies and outliers. As the study progresses and as perceived risks change, the intensity of monitoring should adapt accordingly, such that resources are always applied to maximum effect. While decreasing cost is a major RBM benefit, in some cases, monitoring intensity can be higher than normal, for example, for a problematic site.
Taking the 'Risk' out of risk-based monitoring
The study manager must assess the risk of error across multiple dimensions as stated below: 
Which sites should be monitored?
Proven investigators usually pose relatively low risk, whereas plausible investigators claim previous study experience with other sponsors, so pose intermediate risk. Potential investigators being new to clinical research pose relatively high risk, whereas problem investigators pose a significant risk. At the start of a study, each investigator and site should be rated for risk, based on the medical condition being studied, protocol complexity, experience with similar trials, and other factors. Also, it should be borne in mind that the situation at a site may have changed recently.
Where should the monitoring be performed?
In general, critical data should be reviewed on-site to confirm data integrity. Less-critical data can be monitored remotely.
When should monitoring be performed?
Monitoring frequency should change as per the site's performance. Analysis of trends could reveal problems; for example, slower data entry may indicate an increase in site workload. An increase in adverse events or out-of-window visits suggests the need for more monitoring.
What type of data should be monitored?
Critical data that deserve the most attention relate to eligibility criteria, informed consent, primary and secondary endpoints, safety, investigational product accountability, and data that would be the focus of an FDA inspection. A site might be very good at data collection but could lack experience with regulatory documents, so the focus of the monitoring needs to be adjusted accordingly.
Remote monitoring does not allow inspection of original paper documents but it helps to identify trends, anomalies and outliers.
The FDA has opened the door to more intelligent monitoring strategies based on risk assessment and management. Adopting RBM is essential to move the clinical research enterprise forward. RBM will help us achieve better compliance and higher data quality, and also change the very way we think about clinical research, with significant impacts across the entire process. However, effective RBM requires a fundamental understanding of risk and how to manage it in clinical studies. For a more effective implementation, three critical factors play a key role, that is, changing mindset, planning and focus on training and education.
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