Risk-Based Monitoring: The Right Solution for a Turbulent Present and an Uncertain Future
Amidst the human tragedy of the current pandemic, clinical trials must go on as sponsors strive to develop and deliver life-saving treatments. While the impact of the pandemic on clinical trials has been massive, the requirements for safeguarding patient safety, data quality and study integrity remain as critical as ever. What has changed, however, is the ability to monitor trials in normal ways. How can the industry adapt? And what are the implications for the conduct of future studies?
It goes without saying that every aspect of the healthcare ecosystem is under enormous pressure, perhaps none more than the sites that are simultaneously treating patients while conducting trials. Within this context, it is essential that the burden on the sites and investigators be mitigated to the greatest degree possible. Further, sponsors involved in researching COVID-19 vaccines and treatments, in particular, must find ways to dramatically accelerate cycle times, with expectations for delivery not in months, but weeks. These demands are challenging all aspects of study design and critical path management.
While there has long been a trend toward decentralized trials and remote monitoring, largely aiming to increase efficiencies and speed up operational processes, industry adoption has been somewhat prolonged. That will surely change moving forward as the barriers of the past are overcome. Further, these trends, and the current situation, indicate far more widespread use of a risk-based monitoring (RBM) approach today and in the future.
In short, risk-based monitoring is the process of ensuring the quality of clinical trials by identifying, assessing, monitoring and mitigating the risks that could affect patient safety and study quality. Essentially, the RBM process determines risks to avoid, risks to accept, risk-control measures to be established and a plan for the conduct of the study. While the FDA and other regulators advocate and even require an RBM approach, there is no prescribed methodology. At Parexel, we view RBM as a practice involving people, process and technology.
Data-driven monitoring techniques combined with central monitoring of aggregated site data, including central statistical monitoring, are key components. Both elements are important.
- Data-driven monitoring provides near real-time insights into how the site is conducting a study: how they are accumulating data and treating patients. It is a proactive review, designed to detect risks in site performance and enable early intervention to mitigate any emerging risks.
- Central monitoring is a lag activity designed to review the accumulated scientific and medical data for the emergence of risk, trends, outliers, variance, propagation and other atypical data.
Following are some of the ways that RBM can help support the “new-normal” monitoring paradigm for new and existing studies.
Reduced On-Site Visits by CRAs
Reduced on-site monitoring visits by clinical research associate (CRAs), whether as a direct result of the pandemic or by design, presents an immediate opportunity to improve patient safety and data quality while limiting associated travel. Simultaneously, sites can better comply with local social distancing practices and restrictions. The key is to determine where oversight can be accomplished effectively from a remote location.
Many risk indicators can be mitigated via remote contacts with the site – for example, query resolution rates and proper reporting of serious/adverse events (S/AEs). Risk indicators in this category include:
- CRF completion timelines
- S/AE and AE rates
- Low AE reporting rate
- Missing eDC pages
With real-time insights into the emergence of risk at sites, CRAs can drill down to the source measures, ensuring that the team is proactively managing evolving risks to ensure patient safety, protocol compliance, regulatory compliance and data integrity. Upon review of these risk indicators, the need for additional site interventions by the CRA can be determined.
Where on-site visits are indicated, CRAs can devote on-site time to critical activities that benefit from face-to-face contact, such as site personnel training, mentoring, and relationship-building with investigators and site staff. These activities will become essential to accelerating cycle times, as strong relationships, teamwork and trust streamline communications.
Key benefits of RBM implementation include:
- Quick identification of emerging trends on potential risks across sites
- Better control over resources, as resources are directed according to work/risk parameters
- Easy identification of sites exhibiting high risk, allowing quick actions by the site management team impacting safety of the subjects and collection of safety data for the studies
- More on-site time spent on Source Document Review (SDR) and ensuring adherence to critical study processes and GCP than on Source Data Verification (SDV)
Risk of Missing Pivotal Visits and Assessments
Patients themselves are following local guidelines and mandates for suspending travel and potential exposure to the virus. For clinical studies, that presents a serious risk of missed pivotal visits and assessments. The result could be a lack of statistical power for the study and an inability to prove the effectiveness of the treatment.
Risk-based monitoring, in particular central monitoring, enables the study team to detect a trend towards a high level of missing pivotal data and take appropriate action. It may be necessary to recruit more patients or extend the study. Alternatively, it might be possible to find ways to safely transport patients to the site for pivotal visits or enable a virtual trial visit from the investigator
Ensuring Data Integrity and Fraud Detection
There has long been concern about the quality of data and overreliance on SDV as a primary method of data quality control. Traditional SDV practices treat all data points in the same way, assigning equal value and status. Whilst this approach is capable of detecting transcription errors, it is incapable of detecting missing or erroneous source data, or differences within and between study sites, thus failing to prevent many data-quality issues. Further, in the current climate, given short staffing at the sites and general levels of stress, there is potential for data to be collected or entered inaccurately because of haste, poorly maintained equipment, sloppiness or fraud.
Central monitoring technology can employ highly tuned statistical algorithms to detect the homogeneity of data across patients, investigational centers and regions to determine instances of potential fraud, identify unintentional errors and pinpoint atypical population patterns. This allows users to take correct action and increase the acceptability and integrity of the data.
Preparing for the Future
In these uncertain days, no one can foresee the future with complete clarity. But one thing is beyond dispute: the conduct of clinical trials will change. Already, recent years have seen a significant move toward patient-centricity, adaptive designs, synthetic control arms and decentralized trials. Those trends are sure to continue, along with constant need to accelerate development cycle times. Deployment of advanced RBM technology and processes can enhance the drug development landscape. Adopting appropriate RBM processes and technologies can help sponsors improve the predictability of study results, patient safety and data quality by indicating where and how to adapt their practices to meet the challenges of the future.
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