The US Food and Drug Administration (FDA) recently expanded on its recommendations for taking risk-based approaches to clinical trial monitoring in a new draft guidance.
Structured as a question and answer (Q&A), the document builds on the agency’s risk-based monitoring (RBM) guidance and is open for comment until May 14, 2019.
Patrick Hughes, chief commercial officer, CluePoints, said the Q&A reinforces the importance of performing a risk assessment before any studies are initiated, “not just large Phase IIb or Phase III trials as the popular misconception seems to be.”
As it pertains to documentation, Hughes told us, “the FDA is really insisting on the fact that you need a process to document everything that you have done, all the issues that you have identified, what you have done about them and when and what the final result is.”
“Sponsors also should consider monitoring risks that are less likely to occur but could have a significant impact on the investigation quality," the guidance reads.
Such data quality oversight employs “a boil-the-ocean approach” to ensure “all important anomalies are surfaced for further review,” explained Hughes. This method has revealed cases of impropriety at clinical sites, he said, enabling actions to be taken to exclude certain data.
The draft guidance also stresses the FDA expectation that companies undertake focused risk assessments and implement risk controls. “This is the message that has been given for many years now,” said Hughes. “However, I believe that you should not only focus on what really matters, but also focus on what is less likely to be a risk.”
As Hughes explained, this depends on the techniques employed to identify and address risks.
“Treating all data equally and analyzing everything means that when you find those elements that are anomalous, such as data being entered at seemingly strange times of the day, you can focus your attention on why that has been flagged as an anomaly as it may transpire that is what really matters,” he explained.
“Hence highlighting the need to explore all possible risks and not just the obvious primary endpoints.”
ICH E6 (R2)
The industry is slowly moving toward adoption of RBM, Hughes said – though the biggest challenge is change in and of itself.
“There is still a huge reluctance to change to something new,” noted Hughes, who said this leads to the second challenge: Evaluating the benefits and value of RBM.
ICH E6 (R2) modernized the ICH Good Clinical Practice (GCP) Guideline, which was implemented more than 20 years ago, and requires that sponsors and contract research organizations (CROs) adopt a risk-based approach to study execution.
While this sparked a paradigm shift – arguably the biggest in decades – not all companies are realizing the financial benefits of implementation RBM, said Hughes, including small and mid-sized companies focused on few products, and in some cases, only one.
He said, “There is a reluctance to take a leap of faith or perceived risk of using another strategy other than the one that they used for many years, as they want to keep performing the same process.”
“Almost all large pharma companies have implemented some sort of RBM strategy, some of them have failed and now they are facing their second iteration of implementing RBM, whereas some of them have been very successful,” Hughes added. “Equally we have seen a rise in CROs catching on to the adoption of RBM as they realize the potential benefits.”
