The final guidance reiterates the main tenets of the original 2011 draft, detailing various risk-based strategies and clarifying that oversight of trials does not have to be entirely performed through on-site monitoring.
The agency notes the “growing consensus that risk-based approaches to monitoring, focused on risks to the most critical data elements and processes necessary to achieve study objectives, are more likely than routine visits to all clinical sites and 100% data verification to ensure subject protection and overall study quality.”
But this type of centralized, risk-based monitoring has been on the minds of CROs (contract research organizations) and sponsors for years.
Lynn King, assistant VP of operations, at Rho, told us the guidance “remains consistent with the original draft published in 2011.
“The guidance is critical as industry faces continuing challenges to execute quality clinical trials with fewer resources and reduced cost,” she said.
On-Site Monitoring
But the push away from on-site monitoring to more risk-based approaches may not be seeing as much of an uptake in the industry because of the high levels of risk aversion.
Mark Shapiro, executive director of clinical development at CRO Clinipace Worldwide, told Outsourcing-Pharma.com that he was not “surprised that there was a call to move away from on-site monitoring. This is because everyone has tended to lay the huge cost of trials on cost of 100% SDV [site data verification] through on-site monitoring.
“I think FDA might have felt that they were being blamed for the high (and increasing) trial costs, even though they never officially said, ‘Do 100% SDV through on-site monitoring,’” he said, noting that risk-based monitoring “makes the most sense right now” in Phase II and Phase IV trials.
“In Phase II, these trials are meant for the sponsor to learn about their drug with enough confidence to make an informed decision about phase III, so their comfort and confidence levels (and budgets) matter,” Shapiro said. “In phase IV, RBM [risk-based monitoring] was never in question. But in early development, I question whether or not many site IRBs [institutional review boards] would be comfortable with RBM by a sponsor during a first in human trial.”
Why the Uptake Has Been Slow
However, CROs and sponsors have not necessarily “moved faster towards remote and central monitoring for at least three reasons,” according to Shapiro:
- Risk Aversion: “Months or years after the trial is over, when the eCTD [electronic common technical document] is submitted, [FDA’s Bioresearch Monitoring Program] is going to physically audit the high-enrolling sites. If they find things that aren’t supported by source, it could jeopardize the data from that site, or even the whole trial,” Shapiro said. “Because of that disconnect, sponsors are going to be very reluctant to take the risk in pivotal studies.”
- Flagging Outliers: Some “types of anomalies are easier to spot remotely looking at aggregate data,” he added. However, “no EDC [electronic data capture] programs that I’m aware of provide that high level flag for data that is an outlier relative to data currently in the database (as opposed to an outlier against a predefined set of criteria).” He also noted many CROs “run these types of checks” in statistical analysis software outside of the EDC system; and
- CRO Business Model: The business model for most CROs “is dependent on on-site monitoring for revenue. I have even heard it described as a ‘cash cow,’” Shapiro said, adding that Clinipace does not “view it that way and the dCRO model is deliberately trying to find ways to provide high quality and reduced cost.”
CRO Oversight
The FDA guidance also makes it clear that if a sponsor transfers monitoring responsibilities to a CRO, the sponsor “should evaluate CRO compliance with regulatory requirements and contractual obligations in an ongoing manner.
“For example, sponsor oversight of monitoring performed by a CRO may include the sponsor’s periodic review of monitoring reports and vendor performance or quality metrics and documented communication between the sponsor and CRO regarding monitoring progress and findings,” according to the guidance.
Shapiro said that from his perspective, the “FDA has already established this point about oversight with actual 483s and warning letters. They basically said that if a CRO messes up, the sponsor is also responsible even when the obligation has been transferred, because if the CRO messed up, they failed to properly monitor the CRO.”
The reasoning behind this view on oversight “remains consistent with the historic approach to oversight, which is that sites, IRBs [Institutional Review Boards], sponsors and CROs, and the FDA all provide different forms of oversight for each other,” Shapiro said.