The risk-based monitoring: what is it?

In a few years, we are seeing a real change in how to make a clinical trial monitoring at the international level.

Indeed, a new risk-based approach was integrated in Good Clinical Practice (GCP, ICH GCP, Section 5.1) and in the European Directive 2005/28 / EC. We talk about « Clinical trials monitoring adapted to risk » (or « risk-based monitoring »).

In this article we will explain you this concept that may seem a bit complicated at first.

1. Regulatory context

In Europe, GCPs were imposed on all the clinical trials of a drug for human use by European Directives 2001/20 / EC and 2005/28 / EC (The GCPs were transposed in French law by the decision of 24 November 2006). They will incorporate many concepts, including that of monitoring.

Definition of monitoring (from the decision of November 2006): "Activity of monitoring the progress of biomedical research and ensuring that it is conducted and the data is
collected and reported according to the protocol, to standards operating procedures, to   the  GCPs and the legislative and to the regulatory provisions in force. "

The monitoring of all source folders onsite has been considered as the standard approach applied by the CRAs for a long time. However, in a few years, a new trend is emerging.

Indeed in 2013, the FDA (Food and Drug Administration) and the EMA (European Medicines Agency) published respectively a guide ( » Oversight of clinical investigations – a risk based approach to monitoring » and « Electronic source data in clinical investigations ») and a reflection text ( « Reflection paper on risk based quality management in clinical trials« , downloadable here), encouraging the pharmaceutical industry to consider a new monitoring approach, the « risk-based monitoring » (RBM).

This approach was created after significant deficiencies in the clinical trials monitoring despite 100% SDV (Source Data Verification) on site. The FDA and EMA have recommended a more centralized monitoring approach, including many performance indicators to identify problems on the research site, and to limit the amount of performed SDV.

The RBM therefore incorporates the concept of risk, incurred by the participant, and is to adapt the pace of monitoring visits of the CRA based on the risk.

2. The Risk Based Monitoring (RBM), what does it consist of?

Unlike “standard” monitoring which checks 100% of the data source and identify errors of data transcription in paper or electronic CRF, the Risk Based Monitoring wishes to optimize and lighten the monitoring.

The intensity of the on-site data checking will then be adapted to the level of risk, predetermined from the beginning of the study in the ‘Risk management plan. “This will allow, among others, to optimize the monitoring on site, so to reduce the time spent in the center, and therefore, the cost attributed to the monitoring. (Almost 30% of the budget of a study is devoted to monitoring!).
This happens notably by the « Remote monitoring » (an article was written about it, you can see it again on the blog by clicking this link: https://blogdelarechercheclinique.com/remote-monitoring/).

Note that the consents audits, eligibility criteria, and safety data (EIG) remain unchanged during the monitoring on site.

In its guide, the FDA encourages promoters to « make global statistical analysis of the study data to identify sites that are aberrant compared to others. » In other words, the promoter can identify centers which data are significantly different from others through statistical algorithms. The promoter will seek to detect incompatible information generated by a center with basing on the data produced by all the other sites participating in the clinical trial

For example, when a center makes a mistakes over several patients, or, when on the opposite, a center never makes mistakes, the promoter must be able to identify it with his software. Thus, the promoter assesses the consistency of data from each center and detects abnormal data to identify specific problems of each center.

Thereby, identifying data gaps, the promoter may trigger a monitoring visit on site, or orientate the CRA on this or that issue to verify at the next visit on site.

Prevent and identify risks (error detection, carelessness, fraud, falsification) as soon as possible thanks to the statistics and then can anticipate and correct the problem before it gets worse.

3. Application of RBM in the AP-HP (Public Hospitals of Paris)

Since 2003, the AP-HP applies risk-based monitoring, depending on the type of clinical trial (with or without medication) and according to the phase of the concerned study, particularly for budgetary reasons.

Click here, You will find below 3 grids used by the AP-HP to set the monitor level (A, B, C, or D; D being the highest level) of a clinical trial:

4. Skills required for the CRA

In RBM, the CRA will incorporate the review of data quality as a whole. For this, the CRA will have to improve and / or strengthen some of his skills.
– Use of statistical software to identify data gaps;
– Interpreting these differences, that is to say, to have an overview on data from the study: to evaluate all the data of a site compared to other sites to see if errors are recurrent and thus correct them quickly.
– Perform the monitoring and remotely (by telephone, remote monitoring, …)
– Write tools to help decision making for different types of risk
– Write a « Risk management Plan »

The initial and continuing training in clinical research will have to adapt to allow CRA to acquire these new skills.

Conclusion :
It has been demonstrated that a high frequency of monitoring on site does not necessarily lead to a better quality of the trail data. By providing more clarity and efficiency, the Monitoring risk-based will be the new standard to be adopted by all CRAs. The new generation of CRAs will have to develop new skills to meet to perform this type of monitoring under the right conditions: proactivity, statistical and analytical skills, etc.

The integration of statistical software in the risk-based monitoring will be essential to the promoter to prevent possible risks, and to help him improving the effectiveness of his monitoring process but also the quality and reliability of clinical data.

Sources :

– Journal of clinical research best practices, Vol. 9, N°9, September 2013, « Adaptive monitoring : Risk-based monitoring and beyond » by Michael Rosenberg
– « Competencies for the changing role of the clinical study monitor : implementing a risk-based approach to monitoring », April 29, 2014 by Charlene Stubbs et al.
– http://www.cluepoints.com/solutions/reduce-regulatory-submission-risk
– http://www.fcrin.org/

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