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:
- Development deadlines, pressure from investors
- Fragmentation of roles into many niche players
- Globalization of clinical trials, complicating the regulatory, business, and scientific/medical environment and patient population.
- Regulatory environment may be over-interpreted, or misunderstood, failing to achieve its actual intent.
- Poor design of studies and study processes.
- Failure to identify priorities.
- Poor risk identification and poor risk mitigation – a lack of use or understanding of risk-management tools and techniques.
- Lack of knowledge or more particularly real understanding of the goals.
Below are some important drivers to Change the Traditional Monitoring Approach to RBM,
Fewer errors:
- Risk-based, centralized monitoring uses more automated reviews to determine the need for manual intervention and is more likely to uncover errors.
Lower cost:
- With centralized monitoring, activities like on-site audits can be limited to study sites where problems are most likely occurring, which can dramatically reduce the cost of monitoring.
Better analysis:
- With all data flowing into a central risk dashboard, statistical and graphical checks can much more easily be used to determine the presence of outliers or unusual patterns in the data.
Cross-site comparison:
- Centralized monitoring also allows you to compare data between sites to assess performance, identify potentially fraudulent data, or locate faulty or non-calibrated equipment.
More timely results:
- A dashboard also makes it possible to identify and resolve issues while the trial is ongoing.
Improving patient safety and data quality.
Complying with regulatory requirements.
Designing Risk-Based Monitoring:
A. Identify Risk:
System Risk:
- Analyze information associated with the environment and its systems to identify potential risks that could indirectly affect a clinical trial.
Project Risk:
- Analyze trial-specific information to identify risks directly linked with the trial.
B. Risk Assessment:
Involves:
- Identifying risks
- Analyzing risks
- Determining the need for modification through controls (e.g., processes, policies, practices)
Develop a monitoring plan to support risk management efforts across the clinical trial or development program.
Considerations for Monitoring Plan:
- Complexity of study design
- Types of study endpoints
- Clinical complexity of study population
- Geography
- Experience of CI and sponsor
- Electronic data capture
- Safety of investigational product
- Stage of the study
- Quantity of data
- Workload at CI site
- Safety profile of IMP
- Characteristics of data to be collected
- Past Experience
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:
- Risks may be acceptable if they have limited impact on subject’s safety, rights, data integrity, and reliability.
- Unacceptable risks require specified risk mitigation actions.
b. Quality Tolerance Limits:
- Define initial acceptable variation or tolerance limits for clinical trial data and procedural metrics.
D. Risk Review:
- Ongoing reassessment of risks by reviewing new information during trial conduct (e.g., pre-clinical data, safety data, updated Investigator Brochure, Protocol Amendment).
- Assess impact on risk management plan and tolerance limits based on trial management outputs.
E. Risk Management Tools:
- Can be paper-based or IT-supported.
- Enable detection, identification, prediction, tracking, and analysis with metric generation.
- Support risk management system and decision-making.
F. Risk Communication:
- Analyze and summarize feedback from the risk review cycle.
- Include measures of measurement variability, assessment of deviations from tolerance limits or protocol requirements, and handling of missing data.
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.