“RBQM is the next RBM” – FDA

“The Risk-Based Quality Management concept is the whole system not just the last component of monitoring” began his speech on July 17, 2019 the FDA’s Director David Burrow in the Robert J. Margolis Center for Health Policy at Duke University. 

He means that today the Risk-Based Monitoring (RBM) is a too short jump for most of the companies. From Risk information other processes within pharma can benefit as well.

This public workshop was to capture stakeholder input on the challenges, barriers, and enablers to implementation of RBM. The workshop also reviewed stakeholder experiences with RBM adoption and opportunities to improve the implementation of RBM. In his presentation FDA’s Director David Burrow specially stressed that he is talking of RBM as a part of Risk-based Quality Management (RBQM) strategy – not a monitoring itself, but a concept aimed at gaining trustful, reliable data.

Risk assessment is the foundation of effective RBM plan.

David Burrow noted that planning and developing of RBM system is a three-part process that begins with risk assessment. “Risk Assessment (RA) – is step one, a necessary component for effective RBM”. RA builds a foundation for the second and third components – developing “well-articulated, clean, crisp clear, appropriate protocol”, and effective RBM plan. To be effective RBM plan must be built on Risk Assessment. “It sounds pretty fundamental but it is a common misconception across the board. People often find that you could take a Risk-based monitoring strategy and put it on top of an already developed protocol. That is not the case. When we talk about Risk-based Quality Management, we talk about these 3 things together,” he said.

Goal of RBM is “To avoid errors that matter”

That is what the concept of “quality” really means. “Quality by Design, Critical to Quality Factors, Quality Risk Management – the common theme there is quality”.  FDA’s director stressed that quality in clinical trials doesn’t mean using Risk-based Monitoring as regulatory compliance. Quality is different and independent from regulatory compliance. Ensuring the absence of the errors that matter is the real aim of RBM. 

At the same time David Burrow emphasized that for being RBM – any type of monitoring (centralized, on-site, or remote) must be implemented “in a risk-based way”. A centralized monitoring does not necessarily mean RBM.  Risk-based Monitoring implies Risk Assessment, well articulated Protocol and a Monitoring Plan tailored to the risks of particular study.

The slight difference in FDA and EMA’s regulatory terminology should not deter from RBM adoption, because all clinical trials stakeholders share the same interest – to avoid errors that matter. 

The FDA’s position is:

Why RBM?

– Quality, reliability, interpretability -> approvability

– Shared interest: The absence of errors that matter

– Regulatory requirement to ensure proper monitoring

What is RBM?

– Varied monitoring activities

  • On-Site
  • Centralized
  • Remote

How to implement RBM?

– Risk Assessment -> Protocol Development -> Risk-Based Monitoring

– Use of monitoring activities in a risk-based manner

– According to a pre-specified plan, based on appropriate assessments, with mitigation, escalation and remediation strategies

As a presentative of FDA David Burrow recommended sponsors to use RBQM strategies in clinical trial as FDA trusts reliable, interpretable, and traceable data. Poor clinical trial data can be a reason for issuing a request for additional information from FDA or recommendation of a third party audit. “All of these things take time. And time equals money. Time of approval of getting new product to the market to added value to the American public,” Burrow warned.

There are two categories of FDA’s recommendations:

  • passive (acknowledging reliability of the submitted data) and
  • active (requiring an enhanced review).

FDA founds that 62 of 334 clinical inspection summaries (CIS) reviews (19%) has at least one active recommendation, most of which do not pose a major challenge. Most of these active recommendations are driven by No Action Indicated inspections(NAI) and Voluntary Action Indicated Inspections(VAI). In this regard David Burrow stressed that quality is driven not by regulatory compliance but by the appropriate protocol. RBM needs to be fit for purpose based on the Risk Assessment.

Burrow noted that sometimes the sponsors claim to have used RBM but it is odds to what FDA considers as RBM, which challenges FDA to assess and track RBM outcomes. At the same time “in some instances where we have seen true RBM be implemented, we have seen a great correlation between the issues that were identified in the Risk-based Monitoring system and the issues we see in the application review on the back end”.

EMA Scientific Administrator Camelia Mihaescu also started her presentation at the workshop with the “broader concept of quality”. She referred back to classical explanation of “quality” in clinical trials as “fitness for purpose, i.e. ability to generate reliable information to answer key questions and support decision making while protecting study subjects”. This information must be sufficient to support good decision making.

How do we build quality in a clinical trial? It could be implemented in approach Quality by Design (QbD):

  • Quality is designed into the study protocol and processes at the very beginning
  • Focus on critical to quality factors to ensure protection of study subjects and data reliability
  • Correct management of the risks related to the critical to quality factors (e.g. implementing a RBQM system)

Camelia Mihaescu pointed that risks in clinical trial should always be considered at 2 levels:

  • trial level (investigational medicinal products, trial design etc.)
  • system level (facilities, SOP, computer system etc.)

Similar to David Burrow, Camelia Mihaescu put an emphasize on the need of a strong connection between monitoring and risk assessment. “Monitoring plan should be reviewed and updated, based on the update of the risk assessment and mitigation plan,” – said the EMA Scientific Administrator. She also  pointed at two key features of good quality clinical trials:

  • Study specific quality management strategy
  • Multi-disciplinary approach to study design

Camelia Mihaescu stressed that to ensure quality is consistently maintained in a clinical trial Risk-based Quality Management should be built into the organization’s quality system and Risk adapted monitoring should be embedded in the RBQM approach.

So, at the workshop devoted to Risk-based Monitoring representatives of the main regulatory agencies – FDA and EMA devoted their presentations mostly to the concept of quality in clinical trials and implementation this concept in RBM. They stressed that focus must be put on the overall Risk-based approach to quality management rather than just Risk-based Monitoring. Proactive approach of Risk-Based Quality Management ensures predictive success of clinical trials.

Watch also: Improving the Implementation of Risk-Based Monitoring Approaches of Clinical Investigations