For the past few years, regulatory bodies, industry advocacy groups, and private companies have been tackling the concept of incorporating risk into the design of clinical trials and customizing monitoring strategies based on those risks to achieve higher-quality outcomes. Regulatory guidance like ICH, and FDA encourage sponsors to adopt advanced concepts of monitoring in clinical research. Risk-based monitoring, centralised monitoring or remote monitoring have been very effective means of monitoring so far. Certainly, there have been magnificent improvements in the quality of the trial, safety of patients, efficiency and cost over the traditional monitoring approach. This article focuses on RBM Methodology as compared to traditional monitoring methods, challenges and rationale for Risk-Based Monitoring (RBM).
During the past two decades, the number and complexity of clinical trials have grown dramatically. These changes create new challenges to clinical trial oversight, particularly increased variability in clinical investigator experience, site infrastructure, treatment choices, and standards of health care, as well as challenges related to geographic dispersion. The current manner in which some elements of a quality system are implemented by sponsors and their agents (CROs etc.) is generally acknowledged to be time-consuming and constitutes a major proportion of the cost of development of medicines.
Initially, the FDA introduced the concept of monitoring in clinical research to oversee the compliance and integrity of trial conduct. This has been a very good initiative for the authenticity of the trial data. However, ICH has taken this to a very advanced level by introducing the risk-based monitoring of trials to focus on those areas where the chance of the error is very high which leads to failure of the trail, compromise of safety and waste of resources. Later, EMA also published the reflection paper and supported risk-based monitoring strategy as very essential tool to enhance the quality conduct of the trial.
Risk-based Monitoring (RBM)
Risk-based monitoring (RBM) is an advanced clinical trial-monitoring technique that not only fulfills regulatory requirements but also moves away from 100% source data verification (SDV) of patient data which reduces workload and leads to a reduction in both time and cost.
Efficient monitoring is critical to protecting the well-being of trial participants and maintaining the integrity of final results. It is now generally accepted that the process for clinical trial monitoring needs to change. A more centralized, risk-based approach is now the preferred method for monitoring clinical trials.
In recent times, technologies have been emerging and taking clinical trials in a more automated world with electronic data capturing (EDC), Clinical trial Management system (CTMS), automation in sample analysis, and Laboratory information management system (LIMS).
Hence, centralized remote monitoring will be the right use of advanced technology in managing risk.
The number of observation/findings from regulatory inspectors and factors mentioned below strongly suggests that the current approach to clinical quality management needs review and reorientation:
Below are some important drivers to Change the Traditional Monitoring Approach to RBM,
More timely results:
Improving patient safety and data quality.
Complying with regulatory requirements.
Designing Risk-Based Monitoring:
A. Identify Risk:
B. Risk Assessment:
Develop a monitoring plan to support risk management efforts across the clinical trial or development program.
Considerations for Monitoring Plan:
C. Risk Control:
Purpose: Reduce risk to an acceptable level.
Prepare and implement a mitigation plan.
Effort should be proportional to risk significance and importance of exposed process/outcome.
a. Risk Mitigation/Risk Acceptance:
b. Quality Tolerance Limits:
D. Risk Review:
E. Risk Management Tools:
F. Risk Communication:
U.S. Food and Drug Administration. (n.d.). Guidance for Industry: Oversight of Clinical Investigations—A Risk Based Approach to Monitoring. Retrieved from https://www.fda.gov/downloads/Drugs/Guidances/UCM269919.pdf.
European Medicines Agency. (2013, November 18). Reflection paper on risk-based quality management in clinical trials. Retrieved from http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/11/WC500155491.pdf.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (2016, November). E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1). Retrieved from https://www.fda.gov/media/93884/download.