White Paper

Planning Quality Into Clinical Trials: Integrating RBM And QbD

Planning Quality Into Clinical Trials: Integrating RBM And QbD

Drug developers are focusing significant attention on risk-based monitoring (RBM) of clinical trials to improve data quality, trial efficiency and patient safety. Widely encouraged by regulatory agencies, RBM adoption is gradually building momentum as sponsors and contract research organizations (CROs) concentrate on developing the right strategies, deploying the most effective technologies and internally managing change.

PerkinElmer Informatics has produced two of a three-part series of white papers on RBM: "Speeding the Switch to RBM" and "The Foundation of Risk-Based Monitoring Success." This paper is part three of the series, presenting industry progress in developing and implementing a systematic approach to RBM, integrating Quality by Design (QbD) and RBM, and change management and planning for broader implementation.

Why Adopt RBM?
With the cost of bringing a drug to market at $2.6B,1 90% of that cost (~$2.34B) is for clinical trials,2 and 30% of trial costs (~$704M) are for site monitoring.3 Considering the escalating costs, length and complexity of clinical trials, life science companies and regulatory agencies have been increasingly supporting RBM as a way to improve clinical trial quality and increase efficiencies. How far have we come? And what lies ahead?

Since RBM represents a significant change in the way clinical trials are monitored, industry adoption is slow. Regulators and industry leaders agree that a systematic potential-risk assessment is the root of planning for RBM. As industry adoption of RBM increases, it is clear that successful implementation requires developing new roles, analytics, and processes among stakeholders.

The benefits of RBM are that clinical trial teams will identify and mitigate risks early or even prevent them entirely, by building quality and risk management approaches into trial design and conduct. They will have a clear view of risks throughout trials and be able to make appropriate decisions and take actions to manage risk, ultimately benefiting patients. The benefits will be measured by selected key performance indicators (KPIs), measuring monitoring efficiency, critical data quality, patient safety, team and investigator satisfaction, and process adoption.

Integrating QbD and RBM
RBM calls for building data quality into the protocol right at the beginning, ensuring patient safety, and improving the use of clinical research associate (CRA) time at the site. The approach enables CRAs to be more focused during site visits, rather than spending most of their time on source document verification (SDV), a costly time- and resource-intensive practice.

While RBM aims to enhance patient safety, improve clinical data quality, and drive efficiencies, the long-standing practice of SDV has shown a minimal effect on data quality. In fact, Medidata found that after observing several thousand studies in its metrics warehouse, the median correction rate with SDV was a miniscule 2.7%.4 Omnicomm® recently reported that traditional SDV consumes about 50% of the site-monitoring workload, with site monitoring about 25% to 30% of a study budget. That means reducing SDV to 20% can result in significant efficiency, removing up to 12% of the study budget and 40% of the site monitoring workload.

Developing a quality protocol requires identifying and removing risks from the protocol prior to the study. Companies are applying Quality by Design (QbD) principles, using a risk-management framework and tools to proactively identify and manage risks. Based on lessons learned, study teams can pilot the approach and implement the results in routine processes.

A good pathway to RBM and improved protocol quality includes initial cross-functional team meetings to introduce QbD, reviewing protocol for clinical trial quality, risk identification, risk mitigation and prioritization, and reviewing Transcelerate's Risk Assessment and Categorization Tool (RACT). At subsequent meetings, the full study team should meet to discuss risk identification and control measures, risk ranking and prioritization, and identifying the top key risk indicators (KRIs) to monitor.

RACT tools highlight the importance of a cross-functional review and decision making, the ranking and rationale of risks, and the alignment of the RACT with risk mitigation. The tools also provide detailed guidance for an effective central monitoring strategy, based on lessons learned from pilots.

An integrated quality management plan (IQMP) that proactively builds quality into the protocol and other quality plans is ideal. During the trial, investigators should monitor quality and address deviations while identifying new risks and amending the protocol accordingly. The plan is based on ICH Q9, and the methodology must be consistent with regulatory guidance and the emerging ICH GCP E6 R2 addendum.5

Effective data management is essential to incorporating RBM into clinical trials. This means not just managing data, but reviewing it and extracting its value to drive quality and efficiency. The challenges to implementation are overcoming corporate and cultural barriers, improving centrally coordinated data management for more accurate insights, improving the data definition and standardizing data models, and improving operational performance and quality by strategic, integrated information management and delivery models.

Regulatory Guidance for Quality Risk Management: Leveraging Technology
The ICH Q9 guideline provides quality risk management (QRM) standards, beginning with a robust risk assessment, the basis of subsequent planning for RBM. QRM is a systematic process for the assessment, control, communication and review of risks to the quality of a drug product across the product lifecycle. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. ICH Q9 sets the foundation for QRM methods with an innovative, risk-based knowledge system, including risk-management facilitation methods and tools.6

In a QRM system for RBM studies, the QRM group should conduct a preliminary risk evaluation followed by a systematic risk assessment identifying study risks and causes as well as risk control and prioritization. The clinical risk manager (CRM) and RBM team should produce a QRM plan and conduct interim risk reviews to assess the performance of controls and identify new ones. Prioritized, proactive QM approaches to clinical trials are supported by the industry to ensure data quality and human subject protection.

Revision two of the ICH GCP E6 guideline is expected to go into effect on November 1, 2016. Industry experts refer to the addendum as an important milestone in driving adoption of QbD and QRM principles and methodologies in clinical development and advocates the use of new technology tools. The goal of the revision is to encourage implementation of improved, more efficient approaches to clinical trial design, conduct, oversight, recording and reporting while continuing to ensure human subject protection and data integrity. QM is expected to be risk-based, incorporate efficient trial design, and move from paper-based CRFs to consistent use of electronic data capture systems.7

The systems of an RBM study should include next-generation technology with real-time dashboards and data aggregation as well as standard and custom analytics and triggered workflows. Targeted on-site visits are combined with remote and central monitoring, with reduced source data verification (SDV).

Part of the purpose of Revision two is to simplify the design of clinical trials to ensure quality through careful, fact-driven planning and execution, and use innovative approaches to conduct and monitor trials. The RBM approach must be holistic and data-driven, adjusting oversight based on RBM findings. The key is not just to have a plan but to constantly monitor progress against the quality plan and to keep adjusting the course toward the final goal, while documenting all interventions.

While FDA guidelines and new good clinical practice (GCP) guidance from ICH give a basic structure to RBM processes and methodologies, companies still have the ability to design their tools and dashboards with a wide variety of gadgets and monitors to help them anticipate potential risks.

Change Management to Implement an RBM Program

One of the major barriers to RBM implementation is our industry's traditionally slow adoption of change. An adequate change-management plan is crucial to ensure a smooth transition and success of a risk-based quality management (RBQM) program. Addressing this topic, Gilead presented at the 2016 SCOPE Conference, it’s five-step change-management program to implement RBQM:

Step 1. First, assess your organization's goals, resources, budget, plans and workflows, and establish your RBQM mission and objectives.

Step 2. Develop a high-level framework. Build your risk-management program by assessing and prioritizing the development of the tools important to your organization, assessing tool design, planning tool development and impact on workflow, and tracking budget and needed resources.

Step 3. Develop tool and program timelines for tool development, training and launch.

Step 4. Develop a change management plan. The adoption strategy includes the clinical operations senior management team. The RBQM program is shared and discussed with other departments, and tools are piloted using a study. Training strategies begin with general risk management training, followed by tool-specific training and cross-functional champion training.

5. For continuous improvement, work with the development team to make revisions and updates to the tools as needed, continue to provide training and support to key stakeholders, and develop a risk-management working group. Meet with the risk-management champions, and track the budget and resources needed.

RBM Adoption: MCC Survey Interim Results
Addressing current RBM adoption, Metrics Champion Consortium (MCC) has accumulated the results from the 2016 Risk Assessment and RBM Survey8 of its 63 member organizations.The MCC survey indicates that while site visits probably will not decrease (immediately) as a result of increased RBM adoption, other factors will improve. The advances include improved quality oversight, data quality, and patient safety, along with reduced monitoring costs and study cycle times.

The survey results to date, indicate that 68% of companies conduct formal assessments of project- and protocol-level risk prior to study conduct and 43% repeat assessments during conduct. The top five data sources reviewed during the assessment are EDC (83%), CTMS (66%), central labs (60%), interactive recruitment tools (57%) and eTMF (45%).

The survey showed that 42% of organizations now use a risk-based approach to site monitoring and another 33% are using it on a pilot basis only. The top two reasons for implementing RBM are to improve quality oversight (88%) and data quality (85%), while reduced monitoring costs is of lesser importance (79%). Compared to MCC's 2013 survey, quality has significantly jumped as the main reason for utilizing RBM (66% in 2013), with cost reduction remaining about the same.

More than a third of companies utilize RBM to reduce study cycle times, since timeline delays is a top driver of cost. More than 80% of clinical trials experience delays ranging from one to six months, costing companies upwards of $35,000 per day per trial. Only 10% are completed on time.9 Looking at the data early and using RBM before database lock can reduce database lockdown time and decrease unfrozen databases.

As the industry increasingly adopts RBM and the impending ICH GCP E6 (R2), the addendum will provide additional guidance for RBM adoption. We expect to see reduced clinical trial monitoring costs and time with improved data quality.

Questions to ask:

  • Is your company utilizing this holistic, dynamic approach, along with a change-management plan that includes effective tools, training, and continuous improvement programs?
  • Do you have the right programs, processes, and people to get the desired outcomes?

A holistic RBM approach requires that alerts and signals tie to planned and unplanned risks, and people, processes and systems are braided together so that expectations and outcomes are clear, measurable, and can be improved over time.


  1. Cost to Develop and Win Marketing Approval for a New Drug Is $2.6 Billion. Tufts Center for the Study of Drug Development. Accessible at: http://csdd.tufts.edu/news/complete_story/pr_tufts_csdd_2014_cost_study
  2. Fiminska Z. Slashing the cost of clinical trials. eyeforpharma. June 10, 2014. Accessible at: http://social.eyeforpharma.com/clinical/slashing-cost-clinical-trials
  3. Buyse M. New FDA Thinking on Risk-Based Monitoring. Oct. 17, 2013. Clinical Leader. Accessible at: http://www.clinicalleader.com/doc/new-fda-thinking-on-risk-basedmonitoring-0001
  4. Young S. eCRF Data Correction Rates Still a Surprise to Many. Accessible at: http://blog.mdsol.com/ecrf-data-correction-ratesstill-a-surprise-to-many
  5. Addendum – Guideline for Good Clinical Practice E6 (R2) http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Addendum_Step2.pdf
  6. Guidance for Industry: Q9 QRM. FDA, June 2006. Accessible at: http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073511.pdf
  7. Andrianov A, Wilder B, Proupin-Perez M. ICH GCP Goes Risk Based. Applied Clinical Trials, Oct 20, 2015. Accessible at: http://www.appliedclinicaltrialsonline.com/ich-gcp-goes-risk-based.
  8. MCC Risk Assessment & RBM Survey Interim Results 2016
  9. Clinical Trials Forecasting for Finance Professionals. Cambridge Healthtech Institute, 2011. Accessible at: http://www.healthtech.com/zctf/