By Maureen Sullivan
It is about 14 years since the CSM Stretta System (Mederi Therapeutics) was launched as the first endoluminal treatment for patients with gastroesophageal reflux disease (GERD). Its introduction offered an alternative to long-term medical treatment with proton pump inhibitors (PPIs) and an alternative to a Nissen fundoplication, considered major surgery for those more severely affected with the disease.
During this time, several other endoluminal devices entered the GERD market—and most of them failed.
In a 2005 review, the Agency for Healthcare Research and Quality (AHRQ) evaluated the efficacy of four endoluminal GERD devices that were on the market at that time: Stretta (Curon Medical, FDA-approved in 2000), Endocinch Suturing System (C.R. Bard, Inc., FDA-approved in 2001), Enteryx, (Enteric Medical Technologies, FDA-approved in 2002) and the Endoscopic Plication System (NDO Surgical Inc., FDA-approved in 2003).
Of these, Stretta alone survives. By the time the AHRQ published an updated review in 2011, Enteryx had been pulled from the market due to serious adverse events (AEs) and the Plication System was no longer in use. As of October 2013, the manufacturers of Endocinch confirmed that it too is no longer in production.
Why have so many failed?
Although Stretta has lasted the course where others have not, it also has withstood many challenges. Originally owned by Curon Medical, the company eventually went bankrupt and its assets, including Stretta, were taken over by Mederi Therapeutics.
“Curon went bankrupt simply because they were unable to get widespread insurance coverage,” said Will Rutan, CEO of Mederi. “One would think that if the FDA has approved a device … that it is proven to be safe and effective … that that would be good enough for an insurance company. But it is not. Even the federal government—the Centers for Medicare & Medicaid Services that governs Medicare—does not view FDA approval as sufficient for covering Medicare constituents, even though the FDA is a branch of the federal government [as well]. There is no participation or cooperation between these two entities. Incredible, isn’t it?” Mr. Rutan said.
Although medical devices that first enter the market will have enough clinical data to satisfy the FDA that they are “safe and effective,” it is very rare for any of them to have supporting studies longer than two years. “If you ask 10 people [for their definition] of a ‘long-term’ study, you’ll get 10 different answers,” Mr. Rutan said, “but if a product is new, then ‘long-term’ is one year.”
The litmus test of a device is its application in the real world, but the irony is that many of the endoluminal devices that launched did not survive long enough for their efficacy to be established. “Insurance companies by and large judge four years—48 months—to be long term, which is the conundrum of new technology, particularly in the United States,” said Mr. Rutan, who explained that it can take several years to progress from a new idea to a finished device due to the necessity for bench testing, animal testing, meeting FDA requirements for approval and obtaining long-term data.
“That is why so many good technologies go off the market: They are unable to meet the very, very high hurdles required by the insurance companies to gain leverage, because such long-term data [required],” Mr. Rutan said. “And they require Level I clinical data, which are randomized controlled trials, and they require society support in the form of guidelines … so gathering all that is required to get widespread insurance coverage is a 10- to 12-year proposition, and very, very few new technologies have investors who are patient enough to fund it [for that long].”
“For that reason [the funding sources] for start-up medical devices are almost gone. Most of the traditional venture capitalists that would have backed new medical technologies have shifted their focus to technology investments like Instagram and Twitter,” Mr. Rutan said.
Unlike the pharmaceutical industry, most medical device companies are small start-ups with limited financial resources. Raising capital to fund a device is no less difficult in the current climate, according to Mr. Rutan. “We have just completed fundraising and even with the derisking we have done—we have regulatory approval, long-term Level I data, society support and tremendous unmet [market] need—even with all that, it was far and away the hardest time that I’ve ever had raising money for a medical device.” he said.
Adding to this challenge is the belief of some industry stakeholders that the FDA’s requirements for market approval are too excessive. “Both ADVAMED [Advanced Medical Technology Association] and the MDMA [Medical Device Manufacturers Association] have been attempting to get the FDA to loosen up some, because [it has] tightened up what are already stringent requirements,” said Mr. Rutan.
All of the endoluminal devices that have launched since 2000 for the treatment of GERD were approved for commercial use through the FDA’s 510(k) preapproval process, which classifies medical devices as Class II or of moderate risk to patients. (A Class III product, such as the Linx surgical procedure, is considered “high risk” and must go through a different and stricter premarket approval [PMA] process). Under the 510(k) pathway, a manufacturer must prove that its device is “safe and effective,” by determining that it is “substantially equivalent” to a similar or “predicate” device previously approved by the FDA, and which is supported by the manufacturer’s clinical research. For example, in its application to the FDA for approval of its SRS Endoscopic Stapling System, the manufacturer, Medigus, cited the NDO Plicator and EsophyX (EndoGastric Solutions) as predicate devices because they used similar mechanisms of action to perform a partial fundoplication.
Chris Rowland, CEO of Medigus, agreed that the FDA approval process is quite strict but in his opinion, it is necessary. “The FDA is doing its job … there are thresholds in place and the FDA holds companies accountable; [the FDA’s] first [responsibility] is patient safety,” he said.
But the FDA’s reach does not stop with granting PMA: It also has the authority to make postmarketing demands such as device registration, mandatory reporting of AEs, and stipulating certain standards in the manufacturing process. Device manufacturers must consistently be vigilant to ensure that they adhere to these regulations.
“The [FDA has the] ability to look and see how the device is [performing in the market] and say ‘you know, I think we made a mistake—maybe this device shouldn’t have been out there,” said Kenneth K. Wang, MD, FASGE, president of the American Society for Gastrointestinal Endoscopy (ASGE). “The 510(k) process has become much more difficult. Now the FDA is requiring more efficacy data to the point where a lot of [medical device] companies are saying ‘well, why bother with a 510(k)? Why not go in with a full PMA [application] for a new device because pretty much, you have to show the same things. If [the FDA] is making the 510(k) that much more onerous, then what’s the advantage of having that pathway?’”
As president of the ASGE, Dr. Wang, has witnessed firsthand, the difficulties inherent in launching nw devices. “New technology like GERD antireflux devices is often very challenging. It’s almost the same kind of thing you see with drugs. There is usually an attempt to try to market these very quickly, and a lot of it has to do with the way funding is for medical devices: Usually these are not big companies with a lot of resources,” he said.
Insurance companies, as well as physicians, also view securing an endorsement from a professional society such as the ASGE favorably, and the publication of guidelines on a particular device or procedure bodes well for its success. The guidelines, Dr. Wang explained, “is an evidence-based document that looks over a given technology and makes recommendations based on available literature.” However, endoscopists tend to be conservative in their evaluation of new devices because, on average, members of that profession tend to be a little older in age (late 40s to early 50s). According to Dr. Wang, “I think most [of us] evaluate the data that’s out there conservatively, concerning the efficacy of a device. I think [we] examine … if the device makes physiologic sense, [as well as] its efficacy,” he said.
“If you look at Enteryx, the injective device that was pulled from the market voluntarily by the manufacturers … [the procedure] was relatively easy to do … it was a technique that most of us were familiar with … but once it developed some serious complications with patients … you know endoscopists kind of shied away from that technology,” Dr. Wang said.
The publication of guidelines is not in itself a ticket to success. Recommendations come with varying degrees of emphasis, a case in point being the “Clinical Spotlight Review” published by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), in February 2013. Although it gave Stretta the highest (“strong”) recommendation, due to the extent—and the quality—of its long-term data, it gave a “weak” recommendation to EsophyX, an endoluminal GERD treatment that was FDA-approved in 2009.
Dr. Wang explained that in addition to writing guidelines they deem appropriate, the professional societies give advice about the kinds of studies that may help to provide evidence of effectiveness and good outcomes, whether or not the new developments have already gone before the FDA. “[Companies] don’t need to go through societies,” Dr. Wang said, “but generally, societies do a better job of vetting what the evidence is for their devices. You know we can present a more unbiased view than they can.”
Despite the market challenges and the time-consuming process of obtaining insurance coverage, devices can still gain a foothold in the market, albeit slowly, as manufacturers target early adopters of new devices and techniques.
“Some [physicians] require less [clinical] data and some require more, depending on their comfort level—on their ability to adopt a new technology, just like some physicians have iPhones and some still have flip phones,” Mr. Rowland said.
Mr. Rutan also found that the medical profession is open to new technology but that a very limited window exists to get a new product in the door.
“The fact that [devices] are not covered is not an obstacle initially because the market loves new technologies. Many times, it involves doctors and hospitals losing money on [new devices] but they are willing to do that for a short period of time. … [However,] it’s a short-term proposition because before long, you have to have insurance coverage or the product will fail,” Mr. Rutan said.
Even with insurance, the success of a new medical procedure also depends on whether it is fully embraced by the medical profession as an effective, safe and durable treatment option for patients.
Ronnie Fass, MD, chair, Division of Gastroenterology and Hepatology and head of the Esophageal and Swallowing Center at MetroHealth Medical Center in Cleveland, said, “At the beginning, we had a rush of endoluminal approaches. For some of them, I don’t think there were significant data to support their long-term effect and some of them … ended up in the hands of people who were not experienced in using them, resulting in some terrible side effects. To convince people that a technique is effective and durable in the long term, you need at least five years [of data].”
Robert Fanelli, MD, FACS, FASGE, chief of minimally invasive surgery and chief of surgical endoscopy at The Guthrie Clinic, Sayre, Pa., said GERD experts are “searching for a continuum along which to treat patients at various stages of the disease,” and endoluminal therapies offer valid treatment alternatives. “We [tend to] hold them up against the standards established by surgery and I’m not sure that it makes a lot of sense for us to look at endoluminal therapy as competition with a Nissen fundoplication." In carefully selected patients, he said, “A nicely performed, low-risk, endoluminal procedure might be just exactly the thing that they would benefit from,” said Dr. Fanelli, who co-authored the SAGES’ “Clinical Spotlight Review.”
In July of 2013, Medigus, an Israeli-based company, received its first order for the SRS in the United States from Columbia University Medical Center-NewYork Presbyterian Hospital. The unique advantage of the SRS over the endoluminal devices that have tried and failed is its simple approach, Mr. Rowland said. “We know that a Nissen fundoplication works. We know that the partial wrap or the full wrap actually is successful, so we’re not trying to recreate that surgical procedure,” Mr. Rowland said. “Instead we are recreating the direction in which it is performed, so instead of going laparoscopic, we are going endoscopic.”
Interestingly, Mr. Rutan said the reason Stretta has lasted well over a decade is that, in constrast, it did not seek to emulate a fundoplication, relying instead on radiofrequency ablation.
“All the other treatments [that failed] were a variation on a fundoplication … whether you suture it, staple it or put an implant around it, it’s still surgery and there are complications associated with it. Stretta is the least invasive, longest lasting … and has the lowest complication rate.”
Ultimately, a device must survive long enough in the market to have a chance to prove its commercial success. The reasons why so many endoluminal technologies have failed to date could simply be explained as insufficient financing and challenging market forces. “None of them achieved insurance coverage; none of them was around long enough to get the quality of data … or society support that is necessary,” Mr. Rutan said. “It’s very difficult to get something approved or cleared, and it’s next to impossible to get it paid for, regardless of clinical efficacy.”
Drs. Fanelli, Fass and Wang reported no relevant disclosures.