Mechanisms of Failure

Northstar Neuroscience’s recent announcement that its EVEREST trial failed to meet its primary endpoint [see article, p5] was not just a setback for the company. In many ways, it was a hemorrhage for the entire neurotechnology industry. So many observers and investors had been counting on the company’s success in the stroke trial, as evidenced by the considerable amount of venture capital that the firm raised and its successful IPO in 2006. And because Northstar was to have been the first in a line of vendors marketing cortical stimulation devices, there were many who looked to the company as an upstart that could put competitive pressure on Medtronic’s DBS franchise.

Of course, the negative results do not spell the end for Northstar, or even its future in the stroke treatment market. The company will still actively pursue promising applications in tinnitus and treatment resistant depression. But it will be a much harder battle now that regulators, Wall Street, and the media have witnessed this initial disappointment.

While it is far too easy to play Monday morning quarterback, we do hope that the industry will learn whatever it can from Northstar’s experience. In our view, this incident points up the value of elucidating, as specifically as possible, the mechanism of action of a given device or therapy. While it is pure speculation on our part, we have seen significant evidence that stimulation can enhance the phenomenon of cortical plasticity, including studies with transcranial magnetic stimulation and direct current electrical stimulation [NBR Aug07p1].

There is also evidence that reversing polarity can diminish performance. Is it possible that Northstar’s trial introduced both positive and negative effects that cancelled each other out? If so, a better understanding of the interplay between electrode placement and the salient neural circuits might well have helped achieve a different result.

Of course, questions such as these—and related issues of stimulus waveform, electrode geometry, and lead placement—can sometimes only be answered empirically, with willing human subjects serving as a laboratory for future enhancements in therapy. Such was the case with the first users of DBS systems—who unwittingly contributed much to our evolving understanding of the mechanisms of action of DBS, and the etiology of specific movement disorders. We expect the same to be true with the first users of cortical stimulation devices.

Still, vendors would be wise to explore computer models and theoretical explanations for how stimulation exerts its effects whenever possible. This approach would not only help smooth the approval process, it could help vendors fine-tune their pivotal trial participants in a way that maximizes the probability of achieving meaningful results.

James Cavuoto
Editor and Publisher