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By Angela Woodall, Healthcare and Environmental Reporter.

As the number and complexity of clinical trials has increased over the past two decades, so has pressure on regulators to open the door to more efficient and nimble strategies. In particular, sponsors as well as CROs have argued that both goals could be accomplished with a different approach to oversight: risk-based monitoring, which involves identifying risks first then coming up with an oversight method instead of the traditional de facto on-site intensive monitoring.

Finally, in August 2013, the FDA officially sanctioned risk-based monitoring, or RBM. The rationale sounded straightforward when the FDA released the agency’s recommendations in a document called, “Guidance for Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring.” The intent was to encourage a change plus offer guidelines for best practices. But the advisory raised as many questions as it answered and, more than three years later, questions still remain about what exactly risk-based monitoring is and when it’s the right choice. As Nicole Stansbury put it, the FDA guidance opened the door to risk-based monitoring but people are still craving details.

A different approach

One of the most important of those questions was how to define risk-based monitoring.

To start with, monitoring is a quality control tool for determining whether protocols are being followed so that deficiencies can be identified and corrected. The FDA outlines two basic approaches. One is frequent visits to each site to evaluate study conduct and review data and documentation. The hallmark of this tact is source data verification, meaning that monitors cross-check and verify data with original source information. And it’s one of the areas that supporters of risk-based monitoring single out as ripe for automation, which is the hallmark of the other method of monitoring. This alternative allows for strategic off-site monitoring using technology, data collection and analysis based on the highest-risk areas of the study — the elements that if faulty would pose the most risk to participants. The idea is to shift toward remote (or “centralized” as it is called) oversight rather than having monitors traveling from site to site checking records 100 percent of the time.

In reality, the traditional model still has a role in risk-based monitoring which is more of an approach than any one single procedure. The European Clinical Research Infrastructure Network (ECRIN), a nonprofit intergovernmental organization focused on the conduct of multinational clinical trials in Europe, reflects this in its definition: “Risk-based monitoring in clinical trials is the practice of assessing the risks of a clinical study and using this information to decide which monitoring effort is most appropriate.” In other words, risk-based monitoring replaces the traditional approach of frequent on-site visits and 100 percent data source data verification with alternatives that match the nature of the trial.

The right fit?

However, working with a definition that vague is sometimes easier said than done especially when it involves a cultural shift as RBM does. Often sponsors are left wondering whether the approach is right for their study.

Generally speaking, risk-based monitoring is considered a good fit for Phase II-IV studies. In fact, companies and sponsors have been using this approach for late-phase, observational, and device trials for years, according to Ann Meeker-O’Connell, head of risk management and external engagement with Johnson & Johnson’s BioResearch Quality and Compliance group. But there is no hard and fast rule or requirements. Caroline Hurley underscored this in the first systematic comparison of academic and commercial RBM tools for clinical trial monitoring when she wrote that a gold standard does not exist. Rather, because risk-based tools for clinical trials are relatively new, their features and uses vary widely and continue to evolve. This makes it difficult to identify the “best” technique or tool, she wrote.

Rather sponsors and their CROs have to step back early on and identify which sites need intensive hands-on monitoring and which ones can do with less. One that needs more monitoring might be a new site, or an existing one with a new investigator. Another consideration is data analysis, which plays a significant role in risk-based management. Decisions have to be made up front about which data will be collected, who will collect it, how it will be processed and who will analyze it. Fortunately the FDA’s 2013 recommendations include a section dedicated to these decisions, “Factors to Consider when Developing a Monitoring Plan.”  According to the FDA, a monitoring plan ordinarily should focus on preventing or mitigating important and likely risks to critical data and processes. The factors to consider involve a combination of factors include the complexity of the study design; types of study objectives; the clinical complexity of participants needs; geography; the quantity of data; and the relevant experience of the team.

The role of CROs

Once these decisions have been made, it is up to the monitors to deploy them. Usually the monitors are members of a contract research organizations rather than sponsor employees. “Ultimately CROs do most of the monitoring whether it is risk-based or not,” said Association of Clinical Research Organizations spokesman John Lewis. Risk-based monitoring as a method is growing, doubling every year since 2012, but is still at play in a fraction of clinical trials, he said. But CROs are still feeling the need to adapt to the shift with new processes, procedures and skills, especially around data analysis. “It’s not difficult necessarily but it is a change,” Lewis said.  Indeed, Sandra Sather, treasurer of the Academy of Clinical Research Professionals Board of Trustees, said she believes CROs will lead the way in adapting to new methods. To quote Sather, risk-based monitoring is not permission from regulatory authorities to decrease oversight. Instead, “it is about doing certain aspects of it in a better, smarter way, based on aspects of the project and quality systems.”

Angela Woodall, Healthcare and Environmental Reporter

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