On 6th May 2016, a draft guideline of the International Council on Harmonisation (ICH) “General Principles for Planning and Design of Multi-Regional Clinical Trials” was published, the aim being to make global multinational clinical trials safer and more trustworthy
A multi-regional clinical study, where treatment effect is clinically meaningful for all regions being studied, unites various ethnicities within one study protocol. Historically, multi-regional clinical trials (MRCT) were implemented either for rare diseases or for very large numbers of subjects (e.g., cardiovascular trials, spirometry trials, etc.).
Within an MRCT, such aspects as ethnic factors and trial quality are of greater importance.
- Ethnic factors relate to intrinsic (genetic, physiological) and extrinsic (medical practice, culture, environment) characteristics of a population.
- Trial quality necessitates adequate evaluation of intrinsic and extrinsic characteristics, together with applying the same quality standard for all regions.
The role of monitoring and other quality checks is considered to be central to addressing the potential risks of data integrity. The role of centralized monitoring and risk-based monitoring (RBM) is defined as “particularly useful”:
“Centralised and risk-based monitoring may be particularly useful for MRCTs in order to monitor and mitigate the impact of emerging regional differences in, for example, retention compliance or adverse event reporting.” [1, page 9]
“Centralised and risk-based monitoring may be particularly useful for MRCTs to identify variability across regions and sites in protocol compliance, e.g., differences in follow-up, compliance with study medications, adverse event reporting, and/or extent of missing data. Mitigation approaches should take regional differences into consideration.” [1, page 23]
This sends an important signal to all who are running or initiating a global clinical trial. Tomorrow, RBM will be not only a , but expected in multi-regional studies alongside ICH guidance.
The example below shows a geographical risk spread based on safety risk indicators in Sanofi’s multi-regional phase III clinical study:
Example of geographical risk-spread in Sanofi’s multi-regional trial with RBM Platform EarlyBird
Increased variability and a heterogeneous population provide additional risks for data integrity of MRCTs. A correctly configured RBM software (with global risk evaluation features) guarantees effective control over subject allocation strategy, ensures that a clinical trial is still feasible, and provides sufficient information for avoiding regional risks, such as delays among regions, fraud, or sloppiness.
Summing up, ICH has highlighted the practicality of RBM in the context of multi-regional clinical trials. Cultural differences and various ethnical factors often result in diverse data quality and jeopardize the whole study. ICH advises overlooking these geographical risks with a centralized RBM process.
References ICH E17 Guideline: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E17/ICH_E17_draft_Step_1.pdf
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