The International Conference on Harmonisation (ICH) did not change the Good Clinical Practice (GCP) since the mid of the 1990th. However, the scale, complexity and cost of clinical trials increased although the ethical and scientific standards are still valid. The new GCP addendum introduces three main topics: electronic media, investigator responsibilities and sponsor responsibilities. In this article, we will focus on sponsor duties, especially on clinical monitoring.

Clinical trial oversight was always a hard component of GCP for pharma. A team of specialists, called clinical research associates (CRAs), are to visit sites regularly, keeping in mind all the guidelines, clinical protocols and their changes and simultaneously estimate if any misconduct is happening. They feel like a detective who needs to obey the ever-changing laws, tolerating dislike and fighting against dishonesty. In these circumstances, any change of regulations feels like a bad joke. From now on, CRAs have to study additional topics.

However, with a more detailed look at the GCP changes, it becomes clear that the GCP additions, published on 11th June 2015, were designed to make a CRA’s life more analytical and focused.

The main GCP additions concerning the clinical trial oversight process were made in:

  1. Monitoring
  2. Centralized monitoring
  3. Monitoring plan and report

The monitoring process according to GCP Addendum E6 (R2) (GCPA) is now becoming systematic, prioritized and risk-based:

The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. (…) A combination of on-site and centralized monitoring activities may be appropriate. The sponsor should document the rationale for the chosen monitoring strategy. [1]

By this addition, the GCPA fixes the standards already defined two years ago by the (Food and Drug Administration) FDA and (European Medicines Agency) EMA guidelines concerning quality by design, risk management and risk-based monitoring (RbM) [2] [3].

From the moment when the GCPA comes into force, the monitoring within a trial should be guided by previously identified risks. If risks are low, application of centralized monitoring could be appropriate; if risks are high, more on-site visits are needed. The proportion of centralized and on-site monitoring depends on clinical trial peculiarities and should be based on a rationale. Remember that the rationale for the chosen monitoring strategy should be correctly documented. Here, ICH assumes that every sponsor will know the advantages of this or that monitoring strategy and will be able to choose the right balance of these strategies.

Centralized monitoring (CM) is defined as:

…the remote evaluation of ongoing and/or cumulative data collected from trial sites, in a timely manner. [1]

Here, it is important to keep in mind that the outcomes of any CM must be reported—i.e. monitoring findings or decisions in any centralized monitoring process should be captured, audited and archived during a trial and for a certain time afterwards.

A regular routine review of submitted data and allocation of statistical analysis are offered as main tools for CM.

1.    Routine review of submitted data

This method implies identification of missing data, inconsistent data, data outliers, or unexpected lack of variability and protocol deviations. Such identification allows the identification of significant errors in data collection, such as data manipulation or data integrity problems.

2.    Review using statistical analyses

The application of statistical methods for identification of data trends such as the range and consistency of data within and across sites has developed dramatically in recent times. Currently there are a number of automatic cloud solutions for such analysis appearing on the market (e.g. Cyntegrity). According to the GCPA, two main objectives could be achieved with this approach:

  • Analysis of site characteristics and performance metrics
  • Selection of sites and/or processes for targeted on-site monitoring

Here, the GCPA closes the circle with the FDA guidance [2], which proposes targeted monitoring as a strategy for risk-based monitoring (RbM).

Monitoring plan and monitoring report

The monitoring plan should be “tailored to the specific human subject protection”, should guarantee data integrity and should foresee certain actions to avert the risks of a trial. The monitoring plan and report are interrelated. A report should contain sufficient details to allow compliance with the monitoring plan. It is proper to keep risks in mind at each stage of monitoring of a clinical trial. Still, when the GCPA mentions preventive actions for certain risks in the monitoring plan, it is not clear how sponsors should conduct a certain risk assessment, how often and what to do if a risk assessment changes during a trial.

Summary and outlook

Summing up, the new GCPA defines the next level of standards reacting to the main trends in the industry: the extensive costs and higher complexity of clinical trials. The new addendum prescribes to analyse essential risks for patient’s safety and data integrity and adjust monitoring strategy accordingly. Although, 39% of pharma companies and contract research organizations worldwide claim to apply RbM in their practice [4] there is a need of clarification how RbM must be implemented in practice and what proportions of on-site monitoring still expected. For now, it is important to keep in mind that rationale of risk estimation and following actions must be analysed from patient’s safety perspective and properly documented, monitoring plan and report must be integral with each other and reflect identified risks.


[1]ICH, “Integrated addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2),” 11-Jun-2015. [Online]. Available: [Accessed: 16-Jun-2015].

[2]FDA, “Guidance for Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring,” Aug-2013. [Online]. Available:…/Guidances/UCM269919.pdf. [Accessed: 15-Aug-2014].

[3]EMA, “Reflection paper on risk based quality management in clinical trials,” 18-Nov-2013. [Online]. Available: [Accessed: 17-Jun-2015].

[4]L. B. Sullivan, “The Current Status of Risk-Based Monitoring.” [Online]. Available: [Accessed: 23-Sep-2015].