U.S.? EU? ROW?
Regulatory and infrastructure differences between the West and the rest of the world may be off-putting, and language and cultural barriers can seem a bit daunting as well. But there are many reasons sponsors might consider conducting all or part of a trial on other shores.
About 80% of trials are behind schedule. This, said Lara, is due principally to patient recruitment, which, in turn, is driven by appropriate site selection.
There are certainly plenty of cancer patients in North America, yet fewer than five percent will ever access a clinical trial. Whatever the reason for this—whether willingness, access, other therapy, geography, or lack of knowledge—“you’re actually ending up in a very narrow funnel of trying to find those patients,” pointed out Nicholas Kenny, Ph.D., evp, oncology, INC Research.
INC will “pressure test” a drug and study design to determine if it will be acceptable to the physicians and the patients that the sponsor is trying to access, and then look into where to best conduct the trial.
For example, because the North American landscape for lung cancer trials is very competitive, with a lot of very good drugs in development for the same indication, “trying to place a new lung cancer study in North America can be quite difficult,” explained Kenny.
“Whereas if you look at some of the emerging regions, or even Eastern Europe, there are still a large number of patients there that might be naïve to clinical trials, or have not been accessed to the same extent. We would look very strongly at alternative geographies.”
There can be substantial cost savings overseas as well. Investigator and site fees in Asia are about half of those in the U.S., pointed out Gargano, while the costs of providing trial-related medications, investigations, and hospitalizations can drop to as low as 30%.
Similarly, labor costs in general are substantially less, and the fact that the region’s more than four billion people are concentrated around major urban areas makes for lower travel expenses for monitoring the sites as well.
Asia-Pacific hosts many specialty care centers with state-of-the-art facilities, and most of the specialists received post-graduate training in the U.S. or U.K. Nonetheless, she cautioned that to insure that the quality of the data collected is up to international standards, it’s still important to assure that staff training and support systems are in place, or that provisions have been made to invest in such infrastructure.
In emerging regions, constraints tend to be centered around “having enough facility with the institutions—whether it’s the community oncology setting or a large academic center—as well as enough physicians and support staff that have been trained in the execution of the clinical trial,” concurred Kenny.
First in Man
Kenny believes that it’s useful to distinguish between first-in-man trials and later phase studies. Patients in the former are usually very sick, and may be grasping at their last opportunity to get some sort of interventional therapy.
The trials tend to be quite complex in design, and often require a highly specialized group used to dealing with that complexity, and to putting a drug into a patient for the first time without knowledge of what can be expected.
INC places 95% of such trials in academic medical centers in the West “because the infrastructure is in place; we know the centers; we know they know how to deal with it and get through,” he said.
In contrast, there is a different set of issues “once you’ve got a drug through that proof of concept into a global trial,” Kenny noted.
For example, North America treats with multiple lines of therapy for a variety of tumor types, yet other therapies may be too expensive, may not be reimbursed, or may not be available at all in other regions—“so if you have trials looking to develop a complex, targeted therapy, it may not be possible to put that in an emerging region.”
Trialing biosimilars—which the participants pointed to as an emerging trend in the field—flips the cost and availability equation on its head. Most biosimilar trials are conducted in Eastern Europe, Latin America, and other emerging regions where the drug may simply be too expensive or not reimbursed, he said.
“In that setting, the opportunity that is presented to both the patient and physician to go into a trial where they have an even chance of getting a biosimilar drug or the innovator drug to help treat that disease is actually quite attractive.”
There is no one-size-fits-all. “If it’s an area we know will do well in North America, we’ll continue to do the trials here as long as the cost is appropriate,” Kenny concluded. “If it’s an area where we know North America is saturated, we’ll do feasibility analyses and market analyses to figure out where else we can take it.”
There is a trend toward catering patients’ treatments to their individual genetic and epigenetic makeup, in order “to give the treatment only to those patients that should benefit from that treatment,” said Scimega’s director of scientific affairs and strategic project manager Luc Daigneault, Ph.D.
Sponsors are looking for sites that know exactly what kind of mutation patients have, placing an onus on the sponsor or CRO to inform and instruct sites how to screen based on the trials they are participating in. There may even be a requirement to develop a companion diagnostic to pick out the targeted tumor subtype.
One benefit of this trend toward personalized medicine is that far fewer patients are required to achieve sufficient statistical power to demonstrate efficacy. “For Phase III in oncology it used to be 2,000–3,000 patients per trial. For melanoma with the BRAF mutation, they were able to obtain an approval with 300 patients worldwide,” recalled Dr. Daigneault.