The NeuroPace RNS System for neurostimulation use in epilepsy has received a hearty endorsement from the Neurological Devices Panel of the US Food and Drug Administration (FDA) Medical Devices Advisory Committee.
After a day-long meeting on February 22, during which the panel heard study results from NeuroPace Inc representatives, presentations from the FDA, and others, and testimonials from patients and families, the 13 voting members of the committee determined that the evidence shows that the device is safe and effective in patients with partial-onset epilepsy in whom other antiepileptic treatment approaches have failed, and that the benefits outweigh the risks.
The panel voted unanimously that the device was shown to be safe, and all but 1 member agreed that the neurostimulator was proven to be beneficial for patients with partial-onset epilepsy who have not responded to other antiepileptic treatment approaches, with 1 abstention. In addition, 11 members voted that the benefit of the device outweighed the risks, with 2 abstentions.
However, panel members expressed some concerns about adverse effects, such as sudden unexpected death in epilepsy (SUDEP), infections, and psychiatric issues, and some felt that the device should be made available only at specialty epilepsy centers.
Current Pulses
The RNS neurostimulator is implanted into the cranium, where it senses and records electrocorticographic (ECoG) patterns. It delivers short trains of current pulses to the brain that are intended to interrupt the ECoG ictal discharge.
The sponsor is seeking a premarket approval application and provided results of its pivotal study, which included 191 patients who received implants (97 receiving active treatment and 94 receiving sham treatment).
Using a generalized estimating equation, longitudinal, Poisson regression model, the study found that the mean percentage change per month in the frequency of total disabling seizures (simple partial motor, complex partial, and generalized tonic-clonic) during the final 84 days of a blinded evaluation period was -37.9% (95% confidence interval [CI], -46.7% to -27.7%) in the active treatment group and -17.3% (95% CI, -29.9% to -2.3%) in the sham treatment group.
A subgroup analysis showed that the largest reduction in seizure frequency appeared to occur in patients with disabling simple partial motor seizures.
The study met the prespecified primary safety endpoint with an acute (0 to 4 weeks after implantation) serious adverse event rate of 12% and short-term chronic (0 to 12 weeks after implantation) rate of 36%.
The 55 serious adverse events, which included site infections and intracranial hemorrhage, occurred in 23 patients in the combined treatment group to the end of the blinded evaluation period at 20 weeks after implantation. There was a suggestion of more injuries related to seizures in the active treatment group than in the sham treatment group.
As of June 4, 2010, 6 patients had died of SUDEP (8.5/1000 patient-years), 2 of suicide, and 1 of lymphoma. Since then, 2 additional patients have died: 1 of SUDEP and 1 of status epilepticus.
The sponsor noted that the treatment effect was influenced by a "surgical effect" in that an initial improvement was seen after implantation of the device and before initiation of stimulation in both the active treatment and the sham treatment groups.
Second endpoints did not statistically significantly differ between the groups. The observed 50% responder rate was 29% in the active treatment group and 27% in the sham treatment group (P = .73), for a placebo-adjusted treatment effect of 2%. There was also no statistically significant difference in the percentage of patients who had a clinically significant improvement in quality of life.
Meeting attendees heard that no device for epilepsy has been approved in 15 years, and that about a third of patients with epilepsy are not adequately treated. Many expressed the urgent need for more treatment options.
Many panel members agreed there were sources of uncertainty with the presented research. For example, although the sponsor's post hoc model achieved statistical significance, other plausible models yielded similar treatment-effect estimates but statistically insignificant results.
Abdelmonem A. Afifi, PhD, School of Public Health, Department of Biostatistics, University of California at Los Angeles, said he would have liked to have seen data assessed by using a random-effects model. However, as a group, the panel felt that these uncertainties did not greatly affect the overall interpretation of the results.
"Hardest of the Hard"
The majority of the panel felt that the primary endpoint represented a clinically significant treatment effect. "This is the hardest of the hard group if you look at who's in the study; a significant reduction in seizures per month in that group of patients I think is clinically significant," commented Gordon Baltuch, MD, PhD, Department of Neurosurgery, University of Pennsylvania, Philadelphia.
However, members did raise some concerns. Michael D. Privitera, MD, Department of Neurology, University of Cincinnati, Ohio, for example, said he would have been "happier" with a higher responder rate. As well, he said, "if we were able to look purely at stimulation or no stimulation without this post implantation effect, we would see something that would be more clinically relevant."
Panel members agreed that certain patients will probably benefit more from the neurostimulator and others less but that it's impossible to identify these groups with the presented data. Some believed that those who might benefit more are those with higher-frequency seizures.
Michael A. Rogawski, MD, PhD, Department of Neurology, University of California, Davis, Sacramento, expressed a concern that the device be made available only to patients who will derive benefit from it, "because those patients who are implanted who are not benefiting may be subjected to substantial risk." He also said the device should be limited to specialized epilepsy centers that have trained neurosurgeons.
Alicia Y. Toledano, ScD, Biostatistics Consulting LLC, Kensington, Maryland, said the study population "is as close to a real-world population as you could get," and that although subpopulations that would reap more or less benefit probably exist, "I'm not prepared to make post hoc limitations to data judging in subgroups. We studied a group, and it worked."
Jose E. Cavazos, MD, PhD, University of Texas Health Science Center, San Antonio, said that the study population consists of patients with very intractable epilepsy and thus may not exactly be "real world." He agreed there are subgroups who respond better to the device and that postmarket studies need to be done to determine who these responders are.
Although the device doesn't work to the same degree in all patients, and it's linked to some adverse events, the general consensus among the panel was that the data show the device is safe.
Some delegates stressed the importance of training and guidelines for neurosurgeons who will be positioning the device and placing the electrodes.
Issues surrounding protocols were also raised. Regarding the use of parameters in the study, Dr. Cavazos said, "My concern is that there's not enough information provided for selection of detection and stimulation parameters."
Commenting on a proposed 1-year follow-up study, members agreed that this is too short. Most said a minimum of 2 to 3 years would be necessary.
Many of the members said they would like to see further data collected on such adverse effects as depression, hemorrhage, infections, and deaths.
Nirjal K. Nikhar, MD, The Neurology Clinic of Washington LLC, Olney, Maryland, said information on sources of death other than SUDEP needs to be collected. He also would like to see postapproval studies gather further measures on functionality that go beyond seizure frequency (for example, whether the patient is able to go to work or school).
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Cite this: FDA Panel Endorses Epilepsy Neurostimulator - Medscape - Feb 26, 2013.
