New EU Regulations for Clinical Trials

(originally presented by Artem Andrianov on German  EPharma Day)


The new EU Clinical Trials Regulation (CTR) becomes applicable already on 28th of May 2016. It introduces a number of major changes in the clinical trial’s application, operations, documentation, and assessment.  It is very important to get prepared to this change already now in order to avoid difficulties with the future trial approvals in EU.

Although CTR is not taking the direct reference on RbM, it refers to principles of Good Clinical Practice (GCP) and Quality by Design (QbD). These principles are the underlying in RbM as well. Therefore, the author offers to apply RbM as a practical mechanism and process in order to embrace the new EU regulation.

The regulation underlines the interest of subjects and assigns to them an ultimate priority over all other interests.

What tools are available in order to help us in the implementation of the new regulations? The RbM approach offers large flexibility and control for these purposes.

The identification of risks, which appear if the regulation is not correctly implemented, helps to avoid them. How to achieve that? Apply several key risk indicators (KRIs) within the digital infrastructure, which can help to monitor automatically the clinical trial and free your time for the real research.

RbM can be defined rather “narrow” following the FDA’s definition:

  • Remote monitoring (application of technologies to access the data remotely, saving the costs of on-site visits.)
  • Reduced monitoring (targeted Source Data Verification) or
  • Triggered monitoring (monitoring based upon pre-defined triggers, i.e., when risk was already identified)

or “broader”, following the EMA’s definition:

RbM is “preventive clinical trial management approach, which aims to identify, assess, control, communicate and review the risks associated with the clinical trial during its lifecycle in order to guarantee the protection of trial subjects’ rights, well-being, integrity and safety and the assurance of quality of data and the trial credibility.”

In the EMA reflection paper the RbM is more as a risk management, which goes beyond the CRA’s responsibilities.  The author is an advocate of the second point of view (broader), which can be seen as a part of Quality by Design (QbD) approach.

Such broad view on RbM opens it as an ideal framework for helping to embrace the new EU regulation. Data connection to EDC, CTMS and other clinical trial recording systems helps in applying the KRIs relevant for regulation:

  • Control over deadlines: reporting about (S)EAs, (data source CTMS, EDC)
  • Control over compliance with the protocol
  • Control over the informed consent compliance
  • Control over the (S)AE underreporting
  • Control over recruitment and target population
  • Control over the SUSARs
  • Control over the rights and safety of the patient and
  • Fraud & sloppiness detection
  • Reliability and robustness of the data generated

CTR demands “A clinical trial may be conducted only if (…) compliance with the condition is constantly monitored”.

Additionally CTR stresses the patient’s benefits and safety.

The RbM is a tool, where one can adequately monitor the compliance, and trigger the monitoring team if a risky situation occurs. What does the term “patient’s benefits and safety” include?

The patient’s benefits and safety assume the following:

The RbM risk indicators can control many sides of the patient’s safety and by means of that help by embracing the CTR:

  • the informed consent signature time and rightness

When risks triggered, a risk-mitigation mechanism should come in place:

  • Single responsibility for the action coordination
  • To-do plan for further investigation and root cause analysis.
  • CAPA

Still there are some risks, which are hard to control with RbM, e.g.: Manufacturing compliances (labeling requirements, completeness and the adequateness of the investigator brochure) [Article 6, p 16].

Key ‘take-away’ messages

Summing up,

  • The new EU Clinical Trials Regulation underlines patient safety and interests, simplifies the trial registration process and increases data transparency. It stresses the data captured during a clinical trial must be trustworthy and robust.
  • The controlling of the data robustness can be delegated to a data driven RbM, which offers a perfect framework to monitor and avoid risks.
  • It is essential to start gaining experience already now – you gain an important competitive advantage. Lack of competence? – bring the competence from outside.



[1] EMA, 2013. Reflection paper on risk based quality management in clinical trials [WWW Document]. URL