In 2003, neurologist Helen Mayberg of Emory University in Atlanta began to test a bold, experimental treatment for people with severe depression, which involved implanting metal electrodes deep in the brain in a region called area 25. The initial data were promising; eventually, they convinced a device company, St. Jude Medical in Saint Paul, to sponsor a 200-person clinical trial dubbed BROADEN.
This month, however, Lancet Psychiatry reported the first published data on the trial’s failure. The study stopped recruiting participants in 2012, after a 6-month study in 90 people failed to show statistically significant improvements between those receiving active stimulation and a control group, in which the device was implanted but switched off.
Although that decision was “game over” for BROADEN, the story wasn’t finished for some 44 patients who asked to keep the implants in their brains, and the clinicians responsible for their long-term care, Mayberg explained last week to colleagues at a at the National Institutes of Health (NIH) in Bethesda, Maryland.
The episode highlights a tricky dilemma for companies and research teams involved in deep brain stimulation (DBS) research: If trial participants want to keep their implants, who will take responsibility—and pay—for their ongoing care? And participants in last week’s meeting said it underscores the need for the growing corps of DBS researchers to think long-term about their planned studies.
In the case of BROADEN, St. Jude Medical—which was acquired in January by Abbott Laboratories, based in Abbott Park, Illinois—stopped recruiting new participants after researchers estimated that the trial had only a 17% chance of success. Still, the trial continued into a second phase, in which the implanted device was switched on in all participants. By the 24-month follow-up, about half of the 77 remaining participants reported that they were “responding” to the treatment (defined as at least a 40% improvement on a standard depression scale). Nineteen were in full remission.
Before the study began, Abbott agreed to pay the cost of surgically removing the device, which includes two electrodes in the brain and wires that connect them to a battery implanted below the clavicle. And for those who wished to keep their devices intact, the company also promised to supply rechargeable batteries.
But participants bear financial responsibility for maintaining the device should they choose to keep it, and for any additional surgeries that might be needed in the future, Mayberg says. “The big issue becomes cost,” she says. “We transition from having grants and device donations” covering costs, to patients being responsible. And although the participants agreed to those conditions before enrolling in the trial, Mayberg says she considers it a “moral responsibility” to advocate for lower costs for her patients, even it if means “begging for charity payments” from hospitals. And she worries about what will happen to trial participants if she is no longer around to advocate for them. “What happens if I retire, or get hit by a bus?” she asks.
Brain researchers need to think through these issues, agreed the ethicists and neurologists attending the NIH meeting, especially given the growing funding available for DBS research. (One major source has become the Brain Research through Advancing Innovative Neurotechnologies initiative.) NIH does require applicants to include a long-term plan for patients when they apply for funding for invasive device studies, which is evaluated by reviewers. But it doesn't provide prescriptive guidelines. At present, “there is no primer” for researchers or companies designing risky, invasive studies, says NIH neuroscientist Michael Kelly.
One option is to require that participants agree that the devices will be removed at the end of a study, although it is not ethical to force anyone to undergo surgery against their will, says Sara Goering, a bioethicist at the University of Washington in Seattle. That’s consistent with many pharmaceutical drug trials, in which patients typically lose access to an experimental drug after the study ends. But it could be a hard sell for patients desperate enough to undergo brain surgery.
Another difficult question is how long researchers should wait to start such high-stakes trials, in order to reduce the risk of failure, says John Krakauer, a neuroscientist at Johns Hopkins University in Baltimore, Maryland. The BROADEN trial, for instance, could have failed for any number of reasons, he notes. Perhaps the participants were too sick—all had to have failed to respond to at least four other depression treatments, including multiple classes of antidepressant. Or the positioning of the electrodes might have been partially to blame: In a separate study, which began after the BROADEN trial, Mayberg and colleagues discovered that they could improve response rates—by as much as 80% in 24 patients—by fine-tuning the electrodes’ position.
But the BROADEN protocol did not use this refined targeting, as it was not developed when the study began. Instead, the team used a standardized placement of the electrodes guided by computerized tomography and MRI scans. “In retrospect, you could say, well, maybe more of that should have been worked out before the [later phases of the] trial,” Krakauer says.
Along those lines, NIH is now supporting nine early feasibility trials for brain stimulation treatments, including two for depression, says Edmund Talley, program director at the National Institute of Neurological Disorders and Stroke.
There’s another uncomfortable possibility: that the hypothesis was wrong to begin with. A large body of evidence from many different labs supports the idea that area 25 is “key to successful antidepressant response,” Mayberg says. But “it may be too simple-minded” to think that zapping a single brain node and its connections can effectively treat a disease as complex as depression, Krakauer says. Figuring that out will likely require more preclinical research in people—a daunting prospect that raises additional ethical dilemmas, Krakauer says. “The hardest thing about being a clinical researcher,” he says, “is knowing when to jump.”
A forthcoming report from the meeting will also examine other ethical issues researchers might need to consider, including the largely unknown, long-term effects of stimulation on the brain, and how to obtain proper consent from participants.
Update, 1 November, 3:01 p.m.: This story has been updated to reflect additional NIH-funded efforts to support researchers as they develop new brain stimulation therapies.
Correction, 7 November, 3:03 p.m.: This story has been corrected to more accurately reflect Sara Goering's position on the removal of implants after a clinical trial.