By Anina Adelfio, Vice President, Industry Relations, ACRO
On July 17, 2019, under cooperative agreement with the FDA, the Duke-Margolis Center for Health Policy (Duke Margolis) held a public workshop. The event, Improving the Implementation of Risk-Based Monitoring Approaches of Clinical Investigations, aimed to identify opportunities to improve Risk Based Monitoring (RBM) implementation and solicit input on the challenges, barriers and enablers that impact the successful adoption of RBM. The workshop was a collaborative engagement attended by regulators, sponsors, clinical research organizations (CROs), technology providers, clinical research site representatives and other key industry stakeholders. Despite the regulatory guidance documents available on this matter,[i] the current uptake of risk-based approaches to monitoring clinical trials is still lagging. The goal of these discussions was to extend the use of risk-based strategies, which ultimately will support improved data quality and increased patient safety in clinical trials.
Jacqueline Corrigan-Curay gave the FDA’s opening comments for the event. Paying homage to Malcolm Gladwell, she described the workshop as “a real tipping point for risk-based monitoring adoption.”[ii] Her remarks preceded an industry-wide discussion of challenges, barriers, and enablers for RBM adoption.
What RBM is & What RBM is Not
David Burrow, Director for the Office of Scientific Investigations (OSI) at CDER, recognized that the wide variability of terms and definitions used to describe risk-based approaches has led to increased confusion around these already complex concepts. What one company calls RBM, another calls Risk-Based Study Execution (RBSE), and another calls RBx. In practice, these strategies are implemented differently from one company to the next, which adds yet another layer of confusion.
Mr. Burrow made an important distinction that set the tone for the day, asking the audience to consider a larger Risk-Based Quality Management (RQBM) concept rather than just Risk-Based Monitoring. He laid out three aspects essential to any effective RBQM strategy:
- A Risk Assessment (before a clinical trial starts, and ongoing)
- A well-designed and articulated protocol and investigational plan (this should be based on the Risk Assessment)
- A Risk-Based Monitoring plan
As Mr. Burrow aptly put it, what matters is “the whole system of risk-based quality management, not just the last component of monitoring.”[iii] All three elements must be developed with risk-based intentions and quality by design (QbD) principles that are built into the trial before it begins, in the pre-trial planning process. In other words, an organization cannot simply skip to step three and call it RBM.
As Mr. Burrow later clarified, “just shifting to 100% centralized monitoring is not Risk-Based Monitoring. [The FDA has] seen that happen and that’s not what we’re talking about.” He extended this notion to include data sampling without a risk-based plan, “that could be an element of a risk-based plan, but you must do it with intent.”[iv]
The key to success in implementing a risk-based approach is finding the right balance between three factors: data quality, patient safety, and cost efficiencies. When done correctly, an organization can use a risk-based approach to increase data quality and patient safety, all while balancing cost efficiencies. Nicole Stansbury, VP of Global Centralized Monitoring at Syneos Health, laid out the challenges an organization faces when implementing such an approach.
Historically, a “traditional” approach to monitoring a clinical trial was to use 100% Source Data Review (SDR) and Source Data Verification (SDV), which results in very high costs. If you keep 100% SDR/SDV and add a Risk Assessment component, this means a lot more time will go in to identifying challenges in a protocol and the costs to run a trial increase even more.[v] An organization can also add other components, like statistical analysis or centralized monitoring. These powerful tools give access to data visualization and trend analysis in real-time. While they significantly increase both data quality and patient safety, they in turn increase the cost of running a clinical trial.
The trick is to incorporate these new tools and strategies in a way that will bring costs down. To get the balance right, an organization must start with the Risk Assessment piece that Mr. Burrow discussed. The Risk Assessment must be built into the protocol and the overall monitoring strategy and plan. Once the critical data and processes are identified and the corresponding risks are established, you can develop a centralized monitoring strategy combined with a reduced SDR/SDV strategy allowing for less frequent need for onsite monitoring as the trial progresses. This allows you to begin to shift your onsite strategy and move to more remote monitoring of data. The remote data reviews will identify additional areas of focus needed and may trigger additional onsite or remote investigations. At that point, some of those cost efficiencies can come into balance.
The changes an organization has to make to get to this point have to be done intentionally, and in the correct order, for this to work. As Ms. Stansbury pointed out, these pieces must fit together perfectly, so that the whole complex system works smoothly, “like a precisely calibrated watch.”[vi] If you reduce SDV before adding the Centralized Monitoring piece, you have effectively placed the cart before the horse.
Deb Jendrasek, Adaptive Clinical Research Partner at Premier Research, spoke about the extensive change management involved to support a risk-based approach to monitoring. Moral of the story: the amount of support that is needed cannot be underestimated. Ongoing training for cross-functional project teams is essential. Education and training are needed on a macro level so that all project teams have a baseline understanding of the Risk Assessment process. On a micro level, each individual team needs to understand the complexities surrounding certain risks.
This training piece requires an enormous amount of time and resources, but it ensures that everyone involved in a trial understands the complexities around the risks – on both a macro and a micro level. Despite the change management challenges that each organization – and the industry as a whole – are up against, Ms. Jendrasek’s message to the audience: “don’t give up, we’re going to get there.”[vii]
Measuring the Impact of RBM
While there is data available about the current uptake of RBM and its effectiveness, the industry is still grappling with the best way to measure the impact of RBM. Brian Barnes, Director at PPD, explained the limitations around collecting data to accurately demonstrate the prevalence of RBM and the efficiencies gained. One of the biggest constraints in measuring the impact of RBM aligns with Mr. Burrow’s comments pertaining to the lack of common terminology. Across different sponsors and vendors, it is difficult to categorize the varying types of RBM methodologies being used. As a result, quantifying the impact of RBM is difficult to determine. Mr. Barnes also highlighted that limitations caused by systems integrations present another challenge to efficiencies and effective RBM implementation.
Mr. Barnes spoke to the industry-wide conversations that are pushing us all in the right direction. Listening to others’ experiences on what has – and has not – worked is immensely valuable as the industry continues to advance RBM and RBQM.
ACRO’s CRO Forum hosts an ongoing RBQM Working Group, which brings CROs and technology vendors together to advance risk-based quality approaches. For more information, go to acrohealth.org/CRO-Forum
You can find the recording of the entire public workshop here: https://youtu.be/xp8Wp0Upuvo
Current Public Resources on RBM
- Guidance for Industry: Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring (2013)
- E6 R(2) Good Clinical Practice: Integrated Addendum to ICH E6 (R1) (2018)
- FDA Draft Guidance: A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers (March 2019)
- E8 (R1) General Considerations for Clinical Studies (Just released in July 2019, Open for public comment through September 2019)
- OECD Recommendation on the Governance of Clinical Trials (2013)
- EU GCP IWG Reflection paper on Risk Based Quality Management in Clinical Trials (November 2013)
- Regulation (EU) No. 536/2014 of the European Parliament and of the Council (April 2014)
- Risk Proportionate Approaches in Clinical Trials – Recommendations of the Expert Group (April 2017)
[i] See 2019 list of FDA and EMA resources listed at the end of this post
[iii] Duke Margolis; 12:00 in video
[iv] Duke Margolis; 3:25:24 in video
[v] Duke Margolis; 51:20 in video
[vi] Duke Margolis; 59:56 in video
[vii]Duke Margolis; 3:16:20 in video