Navigating Complexity: Sites Adapt to Evolving Trial Protocols
As the clinical trials industry implements more complex trial designs in the quest to achieve greater speed and efficiency, sites must be nimble enough to take on the retraining and increased protocol amendments that come along with these innovations.
The traditional phased structure of clinical trials is used less and less, especially in oncology, says Lindsay McNair, WCG’s chief medical officer. Master protocols, such as umbrella, basket and platform trials, are increasingly popular because they allow planned changes to trials mid-stream and address multiple scientific questions under a single protocol.
Platform trials, which were essential in evaluating potential COVID-19 treatments during the pandemic, use multiple arms to assess drug candidates at the same time and can drop arms that fail or add additional interventions to study. In umbrella trials, patients with the same disease are given different therapies based on different biomarkers, molecular targets or other characteristics, all under one protocol. And in a basket trial, which can be considered the opposite of an umbrella trial, participants with different indications of disease are grouped together based on a shared biomarker and given an intervention targeted at that biomarker rather than at the disease.
These types of master protocol designs are particularly prevalent in oncology research, which is the most complex therapeutic area and its trials continue to grow even more intricate, noted Suzanne Caruso, senior vice president of clinical solutions for WCG. According to a new WCG analysis, there has been a 19.4 percent increase in oncology trials with three or four arms from 2018 to 2021, while oncology trials with five or more arms have seen a 20 percent increase.
The benefits sites can realize from complex trial designs intended to handle more cumbersome research include the opportunity to communicate more directly and consistently with sponsors, learn from other sites and work with more experienced and knowledgeable trial monitors. But along with those pluses come serious challenges, according to Jessica Moehle, director of operations at the University of Utah Huntsman Cancer Institute’s Clinical Trials Office.
First among those challenges is the greater volume of protocol amendments complex trial designs generate. By their nature, master protocols create change because they are designed to adapt to a trial’s findings as it progresses, such as adding new trial arms. But reporting to and receiving approval from sites’ IRBs for every amendment can be cumbersome.
Moehle strongly advises sponsors implementing more complex trial designs to use a single IRB for all sites. Some local IRBs have struggled to fully understand master protocols, she says, and instead of reducing red tape as intended, they’ve added to it. A strong document distribution system is also especially important in these trials to keep documents well-organized and available to site staff.
In addition, it’s critical that sites treat new arms almost like a new protocol, Moehle says, providing review, training and evaluation for site staff every time a new arm is added to a trial.
And, she says, “There will almost always be additional budget work.” Sites need to allow time and money for assessment, training and implementation of the new arm. “It’s maybe not at the level of a brand-new trial, but some of those same functions still need to be carried out.”
Moehle has found weekly prerecorded training sessions provided by sponsors to be successful because sites can let staff complete them on their own time rather than having to schedule already-busy personnel.
Sites should convene what Moehle calls “mini site initiation visits” for newly added arms, perhaps during research meetings, to discuss and plan for appropriate enrollment and go over any nuances a new arm may have.
Additionally, maintain a sharp eye for inconsistencies in procedures between trial arms and the overall trial. This has been a recurring and challenging issue, she said, because complex trials with many arms don’t always line up with what is described in the trial’s SOPs and it can be difficult to remain compliant when the directions don’t match up.
In a final word directed at sponsors, Moehle implored that they consider the burden use of multiple vendors can place on sites. This is especially true when accessing data directly from proprietary, protected electronic medical records or data warehouses.
Sites can’t review and implement all of the vendor technologies easily, she said. “I know on some of these vendors, it’s taken us almost two years to go through our academic review processes, committees and leaders.”