Innovation Overload? Too Many Novel Ideas May Be Holding Back Progress in Transcatheter Mitral Valve Technologies

LONDON, England—Despite signs that the US Food and Drug Agency (FDA) is increasingly eager to streamline the approval process for high-risk devices, a growing chorus of voices is asking: are there simply too many medical start-ups trying to develop transcatheter mitral valve repair and replacement devices?

The question comes amid growing appreciation of the differences between aortic and mitral valve interventions—a recurring topic during “Innovators Day” here at PCR London Valves 2016.

Asked at the end of the day whether the same swift growth and penetration seen with TAVR can be assumed for mitral valve repair and replacement devices, the consensus opinion among a panel of experts ranging from clinicians to industry observers was an emphatic no.

“Cleary the mitral valve is much more complex, but there are three areas where I think we can learn from the TAVR space,” said panelist Martyn Thomas, MD (St Thomas’ Hospital, London, England). These are patient selection, appropriate imaging, and appropriate caution while learning to do procedures safely, he said.

“We struggled to find the ‘good’ TAVR patient and to not do the futile patients,” Thomas noted. “When I look at the transcatheter mitral space, those first devices really never had a chance because we really didn't know what patient to do.”

As for what can be done technically, he continued: “At least to me, it looks as though transseptal is going to win [as the delivery route of choice] and we’ve sort of discovered that now” after 3 years of innovation and multiple different approaches.

Thomas was careful to remind the audience that important differences remain between the two fields. While there were no good alternatives to TAVR in high-risk aortic stenosis patients, optimal medical therapy can to some degree help patients with severe mitral regurgitation (MR), he noted. “I've been involved [in surgical cases] where the patient is lined up for a procedure, and they come back 2 or 3 months later after they've been optimized and you say, what happened to the MR?”

Beyond Technology—A Patchy Rationale

Karl-Heinz Kuck, MD (Asklepios Klinik St. Georg, Hamburg, Germany), also one of the discussants, pointed out that the challenges go far beyond device innovation and technique. Training, he noted, will be far more challenging than it was for operator learning TAVR. “I think we can train many, many people to replace the aortic valve, but training [for mitral procedures] takes much, much longer. In my department we have done more than 700 [mitral-repair] clip patients now using various technologies and I can tell you, I still have to concentrate every time.” By contrast, “we do a Sapien [TAVR] in 45 minutes,” Kuck reported. “The patient is awake, and it’s nothing special anymore.”

There is another, more fundamental difference that should not be underestimated, Kuck continued. This is the fact that while there are “lots” of data from randomized controlled studies showing that replacing an aortic valve is better than “doing nothing,” there is not the same evidence supporting interventions in mitral valve disease. 

“We know that mitral regurgitation . . . has a negative impact on survival, but we don’t know if fixing it has a positive impact on survival,” Kuck said. That’s mostly because the sickest patients are currently not candidates for surgery. “These new devices will allow us to study this question,” he added. “Maybe 5 years from now we have a huge market or maybe we have a very small market, and that's what needs to be figured out. . . . Who, in the future, will profit from annuloplasty, who will profit from a clip, and who will profit from a replacement?”

Movers, Shakers, and Moneymakers

Larry Biegelsen, an analyst at Wells Fargo Securities (New York, NY), gave the keynote lecture that capped off Innovators Day, focusing on the perspective from worldwide financial markets. He pointed out that there has been a 56% increase in the number of Class III (high risk) medical devices approved by the FDA in 2015 as compared with 2014. The TAVR field in particular is seeing a radical reduction in the time to approval for transcatheter aortic valves. FDA review of the first Sapien device (Edwards Lifesciences) took 536 days, he noted, while more recently the agency spent just 60 days to approve the CoreValve Evolut R (Medtronic). Payers, industry, and investors all appear to be willing to pay for—invest in—innovation, Biegelsen concluded.

Indeed, in 2015 three of the biggest medtech companies made headlines with high-profile acquisitions in the mitral space last year: Edwards bought CardiAQ, Medtronic bought Twelve, and Abbott bought Tendyne. Each spent an estimated $400 million despite fewer than 30 patients in total having received one of the three devices. Expressed differently, that’s an expenditure of roughly 40 million per implantation, Biegelsen noted.

But beyond these three companies are between 50 to 60 smaller companies also developing repair and replacement devices. Again and again Sunday, speakers and panel discussants chewed over the question as to whether this abundance of experimental devices—all with different designs, different materials, different anchoring mechanisms, and different delivery routes—is driving innovation or holding it back.

Innovation Overload?

Alexander Schmitz, investment director at the venture capital firm Endeavor Vision (Geneva, Switzerland) and part of Sunday’s discussion panel, described the problem as follows: “Let’s assume all these devices are equally effective and equally safe—they are all unique and all complex in their actual delivery and implantation, and the learning curve that physicians (even very talented and experienced physicians) have to go up is high. Even if you assume equivalent safety and efficacy with these devices, there are just too many mitral devices out there for them to get sufficient [case] volumes, even if the patients were there.”

It’s a situation that Nicolo Piazza, MD (McGill University, Montreal, Canada), speaking in a mitral valve replacement session earlier in the day, termed “innovation overload.”

To TCTMD, Piazza predicted that the within 10 years’ time the “majority” of mitral regurgitation patients will be treated with transcatheter procedures. But in order for that to happen, he said, the field of investigational devices will need to be winnowed down.

“The whole point of innovation overload is that we’re creating discrete pockets of experience with a particular device, and all of these products need to be tested at so-called centers of excellence. So then you have all of these centers of excellence saturated with devices, and you're going to have 2 or 3 centers that are just doing one type of device and doing maybe 10 implantations a year in total.”

At this pace, the field cannot move forward at a reasonable speed, he continued. “All of this innovation may actually be hampering the [advancement] of a particular device”—things like proper technique, patient selection, and device iteration. “With TAVR, there were only two workhorses in the transcatheter aortic field—Edwards and CoreValve—and we were able to really concentrate on those for a good 8 to 10 years before some significant other parties come in,” Piazza stressed. “It may be that all of this innovation [in mitral valve disease] may actually be killing innovation.”

The moderator for the discussion that followed Biegelsen’s talk, David Cassak, editor at MedTech Strategist, took a different perspective but reached similar conclusions.

“Right now there are more companies in this space trying to make sense of this than will find long-term sustainable funding, particularly with the difficulties of patient enrollment,” he told TCTMD. “Time is money. And if you are taking 5 or 6 years to enroll for your clinical trial and then you have follow-up after that, you're going to exhaust the patients and the interest of investors.

“Innovation overload . . . discourages investors from supplying enough capital to have these companies build for the long term,” he continued “And if there isn't the patient population to do the trials, then the FDA is going to suddenly look a lot less friendly. Not because anything is evil going on, but because they don't just have the proof that is going to make them comfortable approving devices.”

While some of the smaller mitral start-ups will get acquired by bigger companies and some may hold their own IPOs, others won’t make it, Cassak predicted. “There are a whole bunch of companies out there who are trying to go so far, and then they run out of options, they have one or two SNAFUS, and all of a sudden, investors start fleeing.”

Most of the physicians and industry observers on Sunday’s panel agreed that while some strategies won’t pan out, innovation is necessary to answer the many unknowns.

“I think most people at the moment don’t know which approach will win, so taking multiple shots on goal is the way forward,” Thomas said.

Looming over the field, however, are questions as to what approach—and whether the aim is replacement or repair—will actually save lives.

“I’ve been advising [companies] to focus on replacement,” cardiothoracic surgeon Gregory Fontana, MD (Los Robles Hospital & Medical Center, Thousand Oaks, CA), said. Repair, in the minds of surgeons, is less of an unmet need and “the burden of proof is on the repair side,” he explained. “In this population, surgical replacement is straightforward. Putting in a valve that doesn’t leak, rather than trying to repair leaflets and modify the leaflet—those are much more challenging and less predictable. I really think replacement is going be the first [approach] to find success.”