William Hyman: Finding the Right Regulatory Balance with Closed-Loop Control

In May, I wrote about a foray into the closed-loop control of drug delivery. In that case, it was a self-regulating propofol sedation system. There is also news that Medtronic is getting closer to FDA approval of a pump that modulates insulin delivery with a sensor that detects dangerous blood glucose levels. The reported results of a clinical trial showed that use of the system improved patient outcomes over manual interventions. A clinical trial is a common part of the FDA requirements for actual proof of safety and efficacy for Class III devices.

As described, the system is short of continuous control in the subdangerous arena. This probably simplified the design of the control algorithm, and it may also be the case that continuous automatic control is of limited value in the absence of danger. Alternatively, it may be that this is an intentional first step chosen for clinical need and/or regulatory reasons, with more general control to follow.

In general, there is a regulatory strategy sometimes used for Class III devices that involves seeking approval for the simplest version of a device first, assuming that this will facilitate FDA approval, and then adding additional functionality through one or more premarket approval application (PMA) supplements. I have heard this strategy described in particular for pacemakers in which more complex functions where designed in but not turned on when first approved. Subsequent features were then added piecemeal—not by additional design, but by turning on what had already been designed. It was further explained that turning things on one at a time allowed for the device to reach a level of performance via several supplements that might have required a new PMA if they had been made available all at once. Indications for use can be another factor that can be rolled out slowly. While perhaps manipulative, this can also serve to facilitate postmarket surveillance of new features without cluttering field performance results with multiple new features simultaneously. In addition, limited claims that lead to quicker approval can allow for an earlier income stream, and the positive acceptance of the technology in the marketplace.

A related regulatory issue is that the closed-loop feature has apparently already been available outside the United States. Thus, if FDA approval is granted, it will be the case that a device was withheld from the American public pending clinical trial results while those in other countries were presumably benefitting from the new technology. Of course, if the clinical trial results had not been positive, it could have been argued that Americans had been protected from a technology that was being marketed elsewhere without adequate testing. This is the regulatory balancing act that affects the FDA, manufacturers and the public. Most of us want just the right amount of regulation, but we can’t definitively define and prove what that amount is.

William Hyman, ScD, is professor emeritus of biomedical engineering at Texas A&M University. He now lives in New York where he is adjunct professor of biomedical engineering at The Cooper Union. Hyman may be contacted at w-hyman@tamu.edu

2 thoughts on “William Hyman: Finding the Right Regulatory Balance with Closed-Loop Control

  1. Yes, Medtronic and several others in the segment have started with a version of the incremental approach. The Low Glucose Suspend (LGS) feature is an example of this, right?

    Vendors wisely took aim at the single biggest risk to patients in the current therapy regime-hypoglycemia. What could be a better starting point than suspending insulin delivery when a calibrated glucose sensor reaches reaches a configurable “low” threshold?

    What could go wrong? The safety and efficacy criteria should be a slam dunk. Three years later, Medtronic is still “getting closer” to FDA approval. I’m not certain I am reading this correctly, but I believe the safely & efficacy framework is making this path *more* challenging. The concern for HbA1C increases – the lab assay to represent 90-day BG control – is being evaluated in clinical trials – and seen as reduced efficacy. It seems that A1C has become such an important outcome criteria that it may be viewed as equivalent – or even more important – than reducing severe hypoglycemia.

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