Risk-based monitoring (RBM) adoption is building momentum as pharma companies and CROs are shifting focus and are developing strategies to develop processes. An insight by Dr Bina Naik, Chief Operations Officer, CBCC Global Research
Clinical trial sponsor’s regulatory obligation is to ensure proper monitoring of investigation at each enrolling site. In order to fulfill this requirement, frequent onsite monitoring visits, i.e., 100 per cent source data verification (SDV) with regularly scheduled monitoring visits has been industry’s long standing practice. These monitoring activities include ensuring that rights and well being of trial subjects are protected, compliance with protocol, proper IP handling and management and verification of accuracy of data entered into the database against the primary source of the data.
This thinking was changed in August 2013, when the FDA introduced the final guidance for a risk-based approach to monitoring in clinical investigations. This guidance supports selective monitoring, provided that the selective approach is justified in a risk-based monitoring plan linked to sponsor’s assessment of operational and patient safety risks. The FDA believes that targeted risk-based monitoring ( RBM) that focus on critical data elements will result in more effective monitoring and help to overcome many of the limitations of on-site monitoring. There is a growing consensus that risk-based approach is more likely to ensure subject protection and overall study quality while improving efficiency.
ICH GCP E6 R2 is an important milestone in driving adoption of Quality-by-Design (QbD) and quality risk management principles and methodologies in clinical development. The revision promotes implementation of efficient approaches to clinical trial design, conduct, oversight, recording and reporting while continuing to ensure human subject protection and data integrity. The new GCP takes evolution of technology into consideration and encourages sponsors to pursue innovative approaches for conducting clinical trials. QbD and risk-based quality management are now recommended as approaches of choice to sponsors of clinical trials.
Beyond the regulatory guidance, the TransCelerate BioPharma consortium (a non-profit organisation focussed on advancing innovation in research and development) has published a position paper with operational analysis, best practices, and practical tools for implementing risk-based monitoring. TransCelerate’s methodology focusses on building quality and risk management approaches into the scientific design and operational conduct of clinical trials to mitigate risk and detect issues early.
While FDA guidelines and new Good Clinical Practice (GCP) guidance provide the foundation to RBM processes and methodologies, RBM adoption is gradually building momentum as pharma companies and CROs are shifting focus and are developing strategies to develop 2 processes and deploy appropriate technology to adopt risk-based monitoring of clinical trials to improve data quality, trial efficiency and patient safety.
Why adopt risk-based monitoring?
Clinical trials are becoming more complex and costly. Various studies have estimated monitoring costs at around 30 per cent of the total study budget. The traditional approach, heavily reliant on exhaustive on site source data verification has proven to be not only resource-intensive, but limited in its ability to identify and prevent issues proactively. The TransCelerate BioPharma consortium member companies conducted a retrospective analysis to assess queries identified via SDV to find the percentage of SDVgenerated queries in critical data. The total was only 2.4 per cent, suggesting that SDV has little impact on the quality of the data.
Risk-based monitoring aims to more efficiently deploy resources across studies based on their specific levels of risk, with the goal of reducing total monitoring resource requirements while maintaining patient safety and data quality.
Some of the benefits are:
- Cost efficiency: Out of the total cost of bringing drug to market, approximately 30 per cent of the cost is site monitoring cost. RBM is the way to improve clinical trial quality and increase efficiencies by reducing low value on site monitoring
- Better quality: As compared to on-site monitoring, ongoing remote monitoring identifies issues earlier, enabling quick resolution and creating strategies to prevent recurrence thereby providing improved quality of analysis. With all data flowing into a central repository it is easier to identify outliers and trends in the data. Access to the centralised data also makes is possible to compare data between sites to assess performance and identify potentially fraudulent data. Centralised data analysis enables cross functional team approach with coordination between monitors, data managers, statisticians, medical monitors, and site staff.
- RBM provides greater compliance with GCP and relevant regulatory requirements
Integrating QbD and RBM
QbD concept is based on the premise that quality should be part of the project planning process. In clinical research the protocol identifies the quality requirements and detailed plans and activities complement what is in the protocol. Key factors to QbD methodologies include a well-designed protocol, proper execution of the protocol, steps to assure protocol compliance, corrective and preventative action methodologies, clear and concise communication strategies, a well designed case report form (CRF) to capture critical data accurately and to ensure uniform data collection across investigator sites.
A good way to integrate improved protocol quality is to have initial cross-functional discussions to incorporate QbD, review of protocol for clinical trial quality, risk identification, risk mitigation and prioritisation.
TransCelerate methodology for risk-based monitoring includes risk assessment, determination of critical data and processes and mitigation of the risks through integrated quality and monitoring plan. The sponsors are encouraged to carry out early and ongoing risk assessment which involves identifying risks, analysing risks and determining whether risk can be modified by implementing control.
Assessments of parameters to identify risks that could affect the collection of critical data or the performance of critical processes is of utmost importance ,to list a few – site characteristics, site performance metrics, (e.g., high screen failure or withdrawal rates, high frequency of eligibility violations, delays in reporting data), complexity of the study design, types of study endpoints, and clinical complexity of the study population; geography, and other factors such as the experience of partners working with each other, use of electronic data capture systems, the stage of the trial .This assessment assists in appropriate resource allocation to areas of greatest need.
No single approach to monitoring is apt or necessary for every clinical trial. FDA recommends that each sponsor design a monitoring plan that is tailored to the subject protection and data integrity risks of the trial. RBM, by building quality and risk management approaches into clinical trial design and management integrates early and ongoing risk identification and mitigates risks early or even prevents them entirely.
The monitoring process with RBM
w Data collection and submission.
A centralised approach requires a steady and reliable flow of data from each study site to the central monitoring system. This will take place through entry of relevant data into an electronic database.
- Back office /centralised monitoring
Centralised monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring and help distinguish between reliable data and potentially unreliable data.
- Identify missing data, inconsistent data, data outliers, unexpected lack of variability and protocol deviations.
- Examine data trends such as the range, consistency, and variability of data within and across sites.
- Evaluate for systematic or significant errors in data collection and reporting at a site or across sites; or potential data manipulation or data integrity problems.
- Analyse site characteristics and performance metrics.
- Select sites and/or processes for targeted on-site monitoring.
- Targeted on-site investigation
Centralised monitoring and further analysis will recommend further requirements of monitoring, recommending traditional onsite visits for source data verification in certain cases.
Challenges to implementation of RBM
Some of the challenges that have prevented companies from moving to RBM include the level of change management required to adopt an RBM approach, lack of experience with and ability to feel confident in data quality if not performing 100 per cent SDV, and lack of industry experience with approval of new drug applications that moved away from the old 100 per cent SDV model. The sponsors will have to take a systematic approach and plan steps towards implementation of quality management framework ensuring overall risk management.
Compared to earlier monitoring methods, like 100 per cent source data verification, RBM clearly demonstrates advantages. Beyond cost saving the obvious benefits of RBM are better quality data, improved timelines and robust patient safety measures. However it is some time before industry to adopt RBM and for the onsite visits to decrease. ICH GCP E6 (R2) will propel the adoption of RBM.
1. Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice (R2) Current Step4 version dated 9 November 2016
2. FDA, August 2013. Guidance for Industry – Oversight of Clinical Investigations – A Risk Based Approach to Monitoring
3.European Medical Agency. (2015) Guideline for good clinical practice E6(R2) 4 – Step 2b
4. EMA, 2013. Reflection Paper on Risk Based Quality Management in Clinical Trials (EMA/INS/GCP/394194/2011)
5. Position Paper: Risk-Based Monitoring Methodology, 2013 TransCelerate Biopharm Inc
6. Andrianov A, Wilder B, Proupin-Perez M. ICH GCP Goes Risk Based. Applied Clinical Trials, Oct 20, 2015.
7. FDA Guidance for Industry: Q9 QRM, June 2006.
8. Quality by Design: Concepts for ANDAs ,Robert A. Lionberger, Sau Lawrence Lee,
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