Skip Navigation LinksHome > March 03, 2011 - Volume 11 - Issue 5 > Should the FDA Rescind the Humanitarian Exemption for DBS?
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Neurology Today:
doi: 10.1097/01.NT.0000395569.87125.ed
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Should the FDA Rescind the Humanitarian Exemption for DBS?

Hurley, Dan

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ARTICLE IN BRIEF

Authors of a paper in Health Affairs argue that the humanitarian device exemption for DBS for obsessive-compulsive disorder should be rescinded, since there is little evidence to support its safe and effective use.

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A paper alleging “misuse” of the FDA's Humanitarian Device Exemption (HDE) for deep brain stimulation (DBS) in the treatment of severe, treatment-resistant obsessive-compulsive disorder (OCD) has spurred impassioned debate among neurologists, psychiatrists, neurosurgeons, ethicists, the device manufacturer, and the regulatory agency.

Disagreements flared over precisely which patients qualify for treatment under the exemption, the true extent of their numbers, and whether they would be better served if the exemption were rescinded.

By allowing the device to be used without the need for a randomized clinical trial of sufficient size to demonstrate statistically significant benefit without undue harm, the exemption “puts patients at risk, limits opportunities for scientific discovery, and gives device manufacturers unique marketing opportunities,” a team of investigators from different institutions, led by Joseph J. Fins, MD, chief of the Division of Medical Ethics at the Weill Medical College of Cornell University in New York City, wrote in a paper in the February issue of Health Affairs.

Perhaps most troublingly, the paper states that the HDE “has implications beyond its application to obsessive-compulsive disorder,” asserting that the case “exposes a market-driven regulatory strategy that could be applied to other conditions to the detriment of scientific discovery, patient safety, and research integrity.”

Under the FDA's HDE, a condition must affect no more than 4,000 patients. In February 2009, the agency granted Medtronic, Inc., an HDE for its Reclaim DBS device “as an alternative to anterior capsulotomy for treatment of chronic, severe, treatment-resistant” OCD.

The approval was based on three studies reporting on a total of 26 DBS treatments conducted worldwide. As summarized in a review paper published this January, the long-term results show “clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient.”

The authors of the Health Affairs paper cite research indicating that OCD affects some 2 percent of the population, and that approximately 10 percent of all patients have the most severe, treatment-resistant form. The authors argue, therefore, that “there are 440,000–660,000 people with chronic, severe, treatment-resistant obsessive-compulsive disorder in the United States alone.”

But both the FDA and a neurologist who specializes in the use of DBS pointed out that the language of the exemption specifies that the device be used “as an alternative to anterior capsulotomy,” a surgical procedure that entails making small, bilateral lesions that target the fibers connecting the ventromedial and orbitofrontal cortex and anterior cingulate with the thalamus, amygdala, and hippocampus. [These fibres pass through the anterior one third of the anterior limb of the internal capsule, which are thought to form part of the fronto-striatal-pallidal-thalamic circuits indicated in the pathology of OCD and depression.]

“I suspect the number of anterior capsulotomies performed annually [as a treatment for severe OCD] would not exceed 100,” said Richard W. Murrow, MD, clinical associate professor of neurology and medical director for deep brain stimulation at the University of North Carolina at Chapel Hill, who was not involved with the Health Affairs paper.

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FEW ELIGIBLE PATIENTS

There is a limited pool of patients eligible for treatment under the HDE, according to the principal investigator of an ongoing multisite, randomized clinical trial supported by the National Institute of Mental Health, which is testing the Medtronic device for severe, treatment-resistant OCD.

“In the real world, there were at most 40 OCD surgeries last year in the United States,” said Benjamin D. Greenberg, MD, PhD, associate professor of psychiatry and human behavior in the division of biology and medicine at Brown University. “About 15 of the surgeries were DBS, the rest were lesion procedures.”

Dr. Brown, the lead author of the review article on DBS for OCD in the January Molecular Psychiatry, said: “You can make the case based on epidemiologic studies that the OCD treatment-resistant population is big, but, in fact, the number of actual candidates for surgery like this is really going to be small. In fact, it's taken us three years to recruit ten patients, and our trial is done at the leading centers with quite a bit of publicity about it.”

But a co-author of the Health Affairs paper said that the HDE issued by the FDA likely made recruitment for any randomized trial of the device more difficult, thereby hindering the accumulation of credible data.

“Patients can now be implanted with the device under the HDE mechanism, without having to be in a clinical trial,” said Helen S. Mayberg, MD, professor of psychiatry and neurology and chair of psychiatric neuroimaging and therapeutics at Emory University School of Medicine. “As such, it will now be very difficult to get the needed scientific data. That's unfortunate because we really don't know, based on 26 people in the published literature, if this is truly safe or efficacious in the long-term.”

Dr. Greenberg acknowledged that the HDE was likely making recruitment of patients to his clinical trial more difficult. Even so, he said: “As a doctor, would I want the HDE not to exist? No. I think this should be a treatment option for very carefully selected patients. While it would be nice to have more definitive data, I think the evidence is pretty clear that this procedure is very promising and actually helpful for many patients.”

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A ‘THERAPEUTIC MISCONCEPTION’

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Another criticism lodged in the paper by Dr. Mayberg and co-authors is that the HDE fosters what it calls “therapeutic misconception,” a confusion on the part of patients as to whether the device is actually a proved therapy or merely an experimental procedure. The paper points out, for instance, that Medtronic's press releases have referred to the device as delivering electrical “therapy.”

“When we think of ‘therapy,’ we think of something that has been proved to be both safe and effective,” said Dr. Fins. “Without a randomized trial offering reliable evidence, I consider this still investigational.”

Both Drs. Murrow and Greenberg agreed that the HDE does not explicitly require that patients be informed of the uncertainty regarding the possible risks and benefits of the device, but noted that it does require IRB approval, which in the case of their own institutions, does require a carefully written informed consent.

The informed consent used at the University of North Carolina, Dr. Murrow said, “directly states that the device does not have standard approval. Without this clear understanding, I agree patients could be ‘put at risk’ of therapeutic misconception.”

Karen Riley, a spokesperson for the FDA Center for Devices and Radiological Health, stated in an e-mail that patients should undergo informed consent. The FDA does not regulate the informed-consent process “because it is part of the practice of medicine,” Riley added.

But Dr. Fins said that the FDA position sidesteps the fundamental question of whether the treatment is in fact a therapeutic practice of medicine or a research endeavor. “You really can't have it both ways,” he said, pointing out the agency's inconsistency in not regulating the treatment under an investigational device exemption, yet still requiring that an institutional review board approve the treatment, as it would any research trial.

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THE RISK OF ADVERSE EVENTS

Another issue raised by the Health Affairs paper is the risk of adverse events that are not adequately assessed, as would be the case in a clinical trial. In a statement released to Neurology Today, Medtronic noted that the company “reports safety information on a quarterly basis to institutional review boards at HDE centers.”

But in treating OCD patients with DBS, there may be unique risks that have not been adequately assessed, said medical ethicist James L. Bernat, MD, professor of neurology and medicine at Dartmouth Medical School.

“I could imagine a situation in which someone would obsess and worry about having an electrode implanted in their brain,” Dr. Bernat said. “Even though the safety has been worked out over thousands of DBS treatments in Parkinson disease, there may be unique problems in the particular pop. of people with OCD. This is the sort of thing that would be discovered in a proper clinical trial.”

Asked whether he thinks the HDE has put the commercial interests of Medtronic ahead of patient interests, as alleged by the paper, Dr. Greenberg said, “I have no doubt that this is part of a commercial strategy of theirs. They're a company.” But both he and Dr. Murrow emphasized their view that the primary beneficiaries will be patients, particularly given a potential market size that, in their view, is tiny.

“I believe there remains an extreme need for compassionate intervention in refractory OCD,” Dr. Murrow said. •

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References:

Fins JJ, Mayberg HS, Nuttin B, et al. Misuse of the FDA's humanitarian device exemption in deep brain stimulation for obsessive-compulsive disorder. Health Affairs 2011;30(2): 302-311.

Greenberg BD, Gabriels LA, Malone DA Jr., et al. Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience. Mol Psychiatry 2010; 15 (1): 64-79. E-pub 2008 May 20.

©2011 American Academy of Neurology

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