Darkness Before the Dawn

The reported results from Functional Neuromodulation’s ADvance study of DBS of the fornix for treatment of Alzheimer’s disease, which showed no significant difference in cognitive scores between treatment and control arms [see article, page 1], is now the latest clinical trial disappointment for the neuromodulation industry. The publication of results from Medtronic’s trial of DBS of VC/VS for depression came as less of a shock, since we’ve known of that failure for some time.

Despite these two discouraging studies, we believe there is still cause for optimism about DBS for psychiatric disorders. The two main reasons for our optimism are the growing knowledge base about the neural circuits involved with depression and the changing attitudes from the FDA about getting novel and urgently needed new therapies to market.

As we report in our coverage of the 2015 NeuroFutures Conference [see conference report, p7], Helen Mayberg from Emory University has helped lay the groundwork for the next clinical trial of DBS for depression by identifying the tracts that are activated in responders but not in nonresponders. And she’s pointed out some tantalizing neural markers for MDD patients predisposed to benefitting from neuromodulation. In the area of memory disorders, Dan Rizzuto from Penn has done similar work looking for biomarkers indicating likely beneficiaries of hippocampal DBS for improving verbal memory. And therein lies the challenge for future clinical trials. Rather than blindly delivering stimulation in one spot in anyone who presents with a particular disorder, trial sponsors would be better advised to cherry-pick the patients with more likelihood of benefit and to fine-tune the stimulation paradigm, using contacts and waveforms that are best suited to the individual patient.

The version 2.0 FDA we have observed in recent months also stands to play a key role here. At the NeuroFutures meeting, we asked Carlos Pena, head of CDRH’s Neurological and Physical Medicine Devices division, whether their new expedited program for life-threatening diseases would include treatment-resistant depression, given the elevated risk of suicide in this population. While the answer that came back was not an unqualified yes, he seemed to indicate that this was a line of reasoning worth pursuing.

So putting this together with previously announced draft guidance from CDRH [NBR May15 p2], we can envision a future expedited trial of DBS for a psychiatric disorder where the participants have been hand-picked by virtue of a biomarker, where the stimulation is tailored to each recipient, where the approval decision can be based on a defined subset of that population, and where the investigators can change their hypothesis if the trial sheds new light on the mechanism of action. Seems like a can’t-miss scenario.

James Cavuoto

Editor and Publisher

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