Renal Denervation’s Demise Highlights CE Mark Inadequacy

I’ve just enjoyed reading the deconstruction of Medtronic’s Symplicity situation, as described by healthcare marketing consultant, S2N Health. You can find the piece here, and interesting it certainly is. What author Amy Siegel points out is that Medtronic’s acquisition of Ardian technologies, for a now-unlikely-sounding $800M, was predicated on the successful CE marking of its Symplicity renal denervation (RDN…Ardian…geddit?) catheter .

Now, obviously it’s not “that” simple, but in some ways you can see how this stuff happens. Amy details Ardian’s original $65 million equity being invested in gaining the CE mark, an exercise that was no doubt dominated by various clinical studies, culminating in Symplicity HTN-2 which included 52 patients in the active treatment arm. Since CE marking and Australian TGA approval and nods from countries that accept either of the above, some 5000 patients have been treated with a therapeutic approach that one randomised sham controlled study now suggests confers comparatively little meaningful benefit…or at least not enough to meet its study endpoint of what is believed to be roughly a greater than ten point reduction in blood pressure in folk with a seriously high starting point.

So, backing up, we have Medtronic shelling out $800 million for a company that has a CE mark and some non-randomised studies. And they weren’t alone. The queue to buy technologies that had a nicely protected bit of intellectual property about them was populated by all the main players. It’s been a feeding frenzy of emperor’s new clothes proportion, and now the dam is leaking and some of these big players are seeking to hold back the waters with claims that one study of one technology shouldn’t be seen as representative of a failure of the entire therapy just yet. One of the big boys, Covidien, has jumped ship early with the announcement that it is pulling its OneShot program. While the company isn’t pointing directly at HTN-3, that’s almost certainly helped make its mind up.

Interestingly it’s not the therapy itself that’s getting the old spotlight treatment, it’s just the bp reducing bit. Renal denervation was never originally thought of as a bp-reducing treatment per se. It was, and still is, understood to have as its main effect, a reduction in heart rate. As a treatment for heart failure and atrial fibrillation, it’s still got legs. In fact, until we see the data, it might have legs in bp reduction too…just not the miracle cure it was promising.

What lessons should be learned here then? Well, the first one is to never trust the data unless it’s worthy of trust. Much of the renal denervation bp data profferred thus far has come from non-randomised, unblinded, no-sham studies. In fact, all of it I think.  We’ve picked up on observations of a few clinician groups’ critiques of this way of going about things. A combination of placebo effect and the vulnerability of those recording single-point, office based bp readings to record what they expect to see, rather than what they truly see, is very likely to have had a massive influence on early outcomes. That’s not a slight on the humans involved by the way…just an acknowledgement of the fact that they are human.

The other lesson, by the way, is a regulatory one. If the HTN-3 study is ultimately upheld as one big nail in renal denervation’s coffin as a bp reduction therapy, it could turn out to be a damning indictment of the current CE marking process. 5000 patients could have undergone treatment costing millions of currency units, all for no significant impact on the thing they went in for. Yes it’s safe, but if it’s not effective what’s the point?

Meanwhile, the FDA, with its wait-and- see approach that has seen no device reach the US market yet, will be smugly pointing to its demand for efficacy rather than just safety. And the thing is, that’s a fair point.

The other thing is…how many other medical devices have reached the EU market based on safety data that has satisfied the demands of the Medical Devices Directive, but with no efficacy data? Or, like Symplicity and other renal denervation systems, data that is far too light on which to base wholesale changes in therapy?

Now let’s see if Medtronic, no doubt licking its wounds, will turn to the other effects of renal denervation for solace. The trouble is, that would all look a bit transparent.  After all, to date the effect of zapping the nerves around the renal arteries on the heart have been strangely ignored in the quest to exploit the bp opportunity and the intellectual property that came with the Ardian acquisition. The intrigue continues.

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