Non-Inferiority Complex

One of the themes that emerged during the 2016 Neurotech Leaders Forum earlier this month [see Conference Report, p7] was the critical importance of clinical trials for novel neuromodulation therapies. As we have witnessed repeatedly in recent years, the success or failure of a clinical trial in a new therapeutic area can have a dramatic effect on the entire industry, and not just the trial sponsors.

As was discussed at the conference, there have been several changes at the FDA that have made the prospect of a successful clinical trial more likely for neurotechnology devices. These include new guidance on patient preferences, altered hypotheses, and subpopulations—as well as a new expedited pathway for life-saving or life-altering technologies. In the U.K., the NHS and NICE recently announced a fast-track process for promising new therapies that have a likely cost of less than £10,000 per quality adjusted life year.

But one aspect of gaining approval for a new neurotech therapy targeted at treatment-resistant disease populations is the inequity inherent in the expectation that a device therapy targeted only at patients who have failed pharmaceutical therapies must achieve the same success rate as a drug targeting the disease population as a whole. During a session devoted to “Drugs vs. Devices,” this editor raised the specter of a hypothetical new device that was more efficacious than any existing pharmaceutical therapy but failed to reach the 50 percent threshold in the refractory population. It seems ludicrous that such a device could be rejected by the FDA while less-effective drugs remain on the market.

As a possible response to this situation, the panel discussed a non-inferiority trial design in which the new neurotech device therapy is compared to an existing pharmaceutical therapy. Such an approach would help level the playing field for device sponsors by granting access to the (presumably) easier-to-treat segments of the disease population. It would also address some of the problems that have plagued device trial sponsors in the past as a result of improper definition of the control group. In this case, the drug therapy cohort would serve as the control group, not some arbitrary placebo. If, as we have long suspected, there is a differential placebo response between a device and drug therapy, this advantage should be taken into account, rather than discarded. We want the patient to get better, don’t we?

A new device therapy approved as a result of this trial strategy would have immediate advantages in labeling and marketing to clinicians. It might also enable clinicians to offer combination therapies to their patients. Finally, it would grant access to patient populations at an earlier stage in the disease progression, which might just lead to better outcomes for patients and providers.

James Cavuoto

Editor and Publisher

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