710 10 NOVEMBER 2017 • VOL 358 ISSUE 6364 sciencemag.org SCIENCE
When a clinical trial of a pharma- ceutical fails, participants usu- ally move on by ceasing to take the drug. But for some people who took part in a trial of a bold, experimental treatment for severe depression, there’s no moving on. Run
by neurologist Helen Mayberg of Emory
University in Atlanta, the BROADEN trial
implanted metal electrodes deep in the
brain in a region called area 25 (Science,
1 November 2013, p. 548). Originally intended for 200 people, the study failed early
on to show a statistically significant effect
on depression and was halted after just
90 participants were treated. Yet 44 of those
patients want to keep their implants, invasive devices that require ongoing medical
attention. The situation has highlighted
a tricky ethical question for Mayberg
and other researchers testing deep brain
stimulation (DBS): Who is responsible for
overseeing—and paying for—such long-term care?
As trials of DBS proliferate for conditions
including obsessive-compulsive disorder
and traumatic brain injury, the challenge
posed by the failed BROADEN study is likely
to become more common. Last month, at a
meeting on the ethical dilemmas of brain
stimulation research at the National Insti-
tutes of Health (NIH) in Bethesda, Mary-
land, Mayberg called on the growing corps
of DBS researchers, and the sometimes new
companies backing them, to adopt a long-
term mindset for studies. “You have to think
about what happens in 5 years, in 10 years,”
she says. “How does a startup make a life-
long commitment to a research subject?”
Drug manufacturers often have to evalu-
ate requests to keep supplying experimental
medicines to clinical trial participants after
a trial ends, even if the company believes
the drug wasn’t a success. But electrically
powered devices implanted in the brain
pose a more complex problem.
BROADEN stopped recruiting participants in 2012, after an interim analysis failed
to show clear-cut differences between those
receiving active stimulation and a group
in which the device was implanted but off.
That was game over for BROADEN—its fi-
nal results were pub-
lished last month in
The Lancet Psychiatry.
The trial’s sponsor,
St. Jude Medical in St.
Paul—which was acquired in January by
based in Abbott Park,
the study began to pay
the cost of surgically
removing the two electrodes in the brain and
the wires that connect
them to a battery implanted below the clavicle. Yet some patients
believe the brain stimulation helped them.
More than 30 trial participants reported that
they were “responding” to the treatment—
defined as at least a 40% improvement on
a standard depression scale—and 19 were in
full remission according to that scale.
The trial participants had agreed in advance to 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. St. Jude
Medical, for its part, had promised to supply rechargeable batteries for the implants.
But Mayberg worries about the burden on
patients. “The big issue becomes cost,” she
says. “We transition from having grants and
device donations” covering costs, to patients
having to pay. Mayberg says she considers
it a “moral responsibility” to advocate for
her trial participants, including persuading
insurance companies to cover the costs of
a depression treatment that isn’t approved
by the U.S. Food and Drug Administration
and “begging for charity payments” from
hospitals. Although St. Jude’s rechargeable
battery has greatly lowered costs, a typical
DBS battery replacement surgery runs any-
where from $20,000 to $50,000, Mayberg
says. She worries about what will happen
to her former patients if she is no longer
around. “What happens if I retire, or get hit
by a bus?” she asks.
Even though U.S. funders such the De-
fense Advanced Research Projects Agency
and NIH are boosting support for tests of
DBS methods or other invasive brain tech-
niques, “there is no primer” about how
to cope with these issues, says NIH neuro-
scientist Michael Kelly. NIH does require
grant applicants to include a long-term plan
for patients in invasive device studies. But it
doesn’t provide prescriptive guidelines.
One option is to stipulate in advance that
devices be removed at the end of a study,
although it is not ethical to force anyone to
undergo surgery, says Sara Goering, a bio-ethicist at the University of Washington in
Seattle. That’s consistent with many drug
trials, in which patients lose access to the
drug after the study. But it could be a hard
sell for patients desperate enough to undergo brain surgery.
A report from the meeting will examine
other ethical issues for researchers experimenting with brain stimulation. Among
them: Can severely depressed people truly
give informed consent for invasive brain devices? Other consent issues arise for people
who are minimally conscious. Researchers
are also wrestling with how to properly inform potential trial participants about the
largely unknown, long-term effects of stimulation on the brain.
Mayberg and others maintain hope that a
DBS treatment for depression will earn FDA
approval. Her next study will actively read
neural activity in area 25 as it gets stimulated, and use that to refine where the electrodes are inserted in participants’ brains.
It’s one of 15 feasibility studies for DBS recently funded by NIH—so the ethical issues
Mayberg and her colleagues discussed last
month won’t go away anytime soon. j
Where surgeons implant electrodes in the brain of a trial participant with
depression is carefully monitored, but what happens after the study is over?
By Emily Underwood
Brain implant trials spur ethical discussions
Who is responsible for invasive devices that clinical trial participants want to keep?
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