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Risk Based Monitoring – Myths and Misconceptions

The publication and implementation of ICH GCP (R2) (Ref 1) has increased the attention of the clinical research industry on Risk Based Monitoring (RBM) and Risk Based Management of clinical trials.  There is now a need to conduct a Risk Assessment for every clinical trial and to produce a Monitoring Plan based on that Risk Assessment.  From what I have observed so far there is still a great deal of uncertainty and discomfort around the process and, while some companies are embracing this with open arms and enthusiasm, others are anxious and unsure where to begin.  There are some myths and misconceptions around which are making this harder and so I would like to try to address and dispel some of these.

Myth 1. Risk Based Monitoring = Centralised Monitoring.

The focus on the benefits of centralised monitoring in the FDA Guidance (2) on RBM led some to conclude that the regulatory agencies want to do away with on site monitoring altogether and this is simply not true.  I still meet people who use the terms Risk Based Monitoring and Centralised Monitoring virtually interchangeably.  They are not the same thing.  In fact in the recently published EMA recommendations document (3) on Risk Proportionate Approaches there is this statement: “On-site monitoring remains relevant in most types of clinical trials, as it is instrumental for the verification of several critical aspects at the trial site, for example adequacy of site facilities, the informed consent process, source data verification and IMP handling on site.”
Risk Based Monitoring means assessing the risks associated with an individual trial and then implementing a Monitoring Plan which helps the sponsor to manage and mitigate those risks.  The Monitoring Plan should include whatever methods, metrics and reports the sponsor considers necessary to ensure the protection of trial subjects and the quality of the data collected.

Myth 2.  The Monitoring Plan should include either exclusively Centralised Monitoring or exclusively On-Site Monitoring.

The two approaches are in no way incompatible and the best Monitoring Plans will usually include a combination of the two methods.  Centralised monitoring provides a better overview of all the data and therefore makes it easier to see trends and anomalies across sites.  On-site monitoring is necessary for certain activities as described above and also promotes a good working relationship with site staff.  A good balance of centralized and on-site monitoring means the on-site monitor can focus on those things which can only be done while at the trial site.

Myth 3.  Once we write the Monitoring Plan we are stuck with it.

A Monitoring Plan should not be a document which is written at the beginning of the trial and then adhered to come hell or high water.  The best monitoring plans will be “adaptive” with milestones and triggers built in which prompt a regular review of the plan and changes implemented where necessary.  For example you could have a Monitoring Plan which front loads the on-site monitoring to establish rapport with site staff, encourage subject recruitment and address issues early.  Once the sites are established and monitors are confident that the trial is on track they could reduce the on-site visits and move more to a centralized approach to get a better overview as the data accumulate.

Misconception 1.  Risk Assessment will just increase costs.

While it’s true that, when done properly, Risk Assessment will take time and resource and therefore money, there is much to be gained by this approach.  By identifying and mitigating risks clinical trials should be made more efficient and issues should be addressed more quickly which should ultimately make trials faster and more likely to reach their goals.  In the longer term this has the potential to reduce costs and allow drugs to reach the market faster.  In order to achieve this we MUST allocate sufficient time and resource to conduct thorough and effective risk assessments, and also we must communicate the resulting information and plans appropriately and include a lessons learned review into the process so that subsequent risk assessments are improved.

Misconception 2.  Risk Based Management of clinical trials is all about monitoring.

The Monitoring Plan is an important part of a Risk Based approach to managing clinical trials, but the Risk Assessment should be applied in many other areas as well.  One obvious example is protocol design, which is why the EMA states that the initial Risk Assessment should be conducted before finalisation of the protocol.  In my opinion we have for too long developed protocols by tweaking the previous one rather than thinking through the design, objectives and methodology.  There is a lot of information collected in clinical trials which is never actually used, and inclusion and exclusion criteria can be unnecessarily restrictive. A really good risk assessment process should allow us to simplify protocols, thus making trials quicker and easier to complete. Other areas which should be informed by the Risk Assessment are Site Selection, IMP management, Safety Reporting, and probably many others.

In summary Risk Assessment has the potential to improve clinical trials, shorten timelines and increase cost efficiency all while meeting the primary GCP requirements for subject protection and data quality. However this is only the case if the process is properly prioritized, resourced and funded - if not then it just becomes yet another pointless tick box exercise.

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1. ICH E6 (R2)

2. FDA Guidance for Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring

3. EMA Recommendations on Risk Proportionate Approaches in Clinical Trials



Jo Burmester
Director of Global Operations, PharmaSchool

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