By Omar Ford, Staff Writer
Biostable Science & Engineering Inc. received FDA clearance for its Haart 300 product, an annuloplasty device designed for aortic valve repair. The Austin, Texas-based company said it will launch the device in select heart centers this summer. The company has had CE mark for the Haart 300 since March 2016. (See Medical Device Daily, March 9, 2016.)
Heart valve repair is a procedure to repair native valve function instead of replacing it with a mechanical or biological replacement device. Valve repair may be more durable than biological valve replacement and avoids the complications associated with anticoagulation medications required with mechanical valve replacement.
Haart 300 replicates the anatomy of the normal aortic valve. The device is designed to resize, reshape, and stabilize the aortic annulus to restore valve competence and help prevent recurrent aortic regurgitation.
"We know that if we could successfully repair the valve instead of replacing it, that it would be a better answer for patients," John Wheeler, president and CEO of Biostable Science & Engineering, told Medical Device Daily. "We hope our technology helps make aortic valve repair an easy or reproducible procedure. We're trying to offer a better patient solution through valve repair."
Data from a study of the Haart 300 indicated that patients who underwent aortic valve repair using the company's device showed significant improvements in aortic insufficiency grade and New York Heart Association scores, with a reported 89 percent freedom from valve reoperation and a 95 percent rate of freedom from all-cause mortality.
Biostable is a private company and was formed in 2008. Wheeler did not discuss specifics regarding Biostable's funding.
However, Wheeler was clear on the fact Haart 300 wasn't targeting patients in the transcatheter aortic valve replacement (TAVR) market.
"From our perspective TAVR really isn't indicated in our patient population for the most part," he said. "Our patients don't have [calcification], which is really a key characteristic of TAVR. Our patients are typically much younger than an aortic stenosis patient."
In addition to aortic valve repair, the company is also eyeing the mitral valve repair market, with its Haart 200 model.
"Patients are extremely young when they develop problems in the mitral valve," he said. "No one wants to put either a tissue valve or mechanical valve in a young patient with a long life expectancy. There is lots of time for problems to develop. A repair solution there would be a really great option."
Biostable said it hopes to file for CE mark approval for the Haart 200 in the near future. Once that process is underway, the company would seek approval for Haart 200 in the U.S.
Treatment of the mitral valve through either repair or replacement has become an attractive opportunity for many med-tech companies. The space has seen a great deal of mergers and acquisitions activity in the past few years.
Late last year, Edwards Lifesciences Corp. took a deeper dive into the transcatheter mitral valve replacement market when it revealed plans to acquire Or Yehuda, Israel-based Valtech Cardio Ltd. for $340 million, with the potential for $350 million in additional milestone payments. (See Medical Device Daily, Nov. 29, 2016.)
With Valtech, Irvine, Calif.-based Edwards gains access to Cardioband, a transcatheter ring technology and sets the company firmly against Abbott Park, Ill.-based Abbott Laboratories' Mitraclip device.
In July 2015, Abbott Laboratories reported plans to pay $225 million for the equity of Roseville, Minn.-based Tendyne Holdings Inc. that it did not already own at the time, making the total deal worth $250 million plus potential regulatory-based milestone payments. The company closed on that deal in September 2015. (See Medical Device Daily, July 31, 2015.)
In a separate deal, Abbott said it had invested in mitral valve repair company Cephea Valve Technologies Inc., of Santa Cruz, Calif., with an option to buy.
Nearly two years ago, Dublin-based Medtronic plc jumped into the transcatheter mitral valve replacement pool and agreed to pay up to $458 million to acquire Redwood City, Calif.-based Twelve Inc. (See Medical Device Daily, Aug. 26, 2015.)
By Omar Ford, Staff Writer
Treatment has begun on the first patients in Origin Inc.'s U.S. dose-ranging GENESIS trial. The Princeton, N.J.-based company has developed a technology to produce and deliver plasma-generated nitric oxide for the treatment of chronic diabetic foot ulcers (DFU).
Origin, which was formed in 2010 and was formerly called Advanced Plasma Therapies Inc., has developed a device with a hand-held, computer-guided system that generates nitric oxide from ambient room air within a defined plasma stream. From there, nitric oxide is generated and targeted toward the patients wound for about six to 12 minutes.
"From an external source, we're able to deliver a critical mechanism to the body, to allow healing to begin," Betsy Hanna, chief operating officer of Origin, told Medical Device Daily.
In the GENESIS study, the company will recruit up to 100 patients across 15 clinical sites in the U.S. After a two-week run-in period, patients will be randomized into one of four different dosing regimens or a standard of care treatment arm to assess efficacy and safety. Patients will be treated over 12 weeks and monitored for 12 weeks post treatment.
Standard for care treatment for chronic wounds includes dressing changes, wound cleansing, pressure relief (off-loading) and wound debridement.
Effectiveness will be measured by wound closure rate and wound closure percentage. Safety will be measured by wound-related adverse events, which include adverse events of all causes that affect the wound. The company said it would provide an update and initial readout of the interim results in 4Q17.
"We're going to do an analysis of the data at the mid-point of the trial to see the differences of the arms and the efficacy vs. the standard of care," Hanna said. "That data will [determine] the time in which we file for a new IDE for a pivotal trial."
Because of the nitric oxide component, the technology is being treated like a combination product by the FDA.
"The FDA has put us in the device division," Hanna said. "But because of the mode of action of nitric oxide, we do have in our review process and our regulatory process members from the [Center of Drug Evaluation and Research] are also involved in the discussions of the safety and efficacy of the therapy."
Plans eventually call for the company to seek approval in Europe.
"Our target initially is going to be looking at wounds that have failed the standard of care," Hanna said. "There are a number of different products out ... [but] nothing with an overwhelming clinical success in treating these kinds of ulcers. You've got a market out there for advanced wound treatment products and the market is more than $13 billion."
She added, "We see this as a wide open opportunity, and our job is to get the first use and indication approved for our device, to demonstrate we can make a difference in that healing."
Origin isn't alone in its goal to get secure FDA approval for a diabetic foot ulcer technology.
One of the most notable companies in the space is Sanuwave Inc. The Alpharetta, Ga.-based firm has been vying to gain FDA approval for its Dermapace technology for a number of years. The device has CE mark approval and uses a noninvasive, biological response for the repair and regeneration of skin, musculoskeletal tissue and vascular structures.
Sanuwave initially hit a major snag in its plans to bring the device to market back in 2011, after it was revealed in the 206-patient trial that there was no statistically significant difference regarding wound closure after 12 weeks between the sham treatment and the treatment with Dermapace. Sanuwave has been notably quiet with its progress in the U.S., but last month it launched a blog on its website to update key developments with its product line.
Integra Lifesciences Holdings Corp. also has applications in soft tissue repair and regeneration applications. The Plainsboro, N.J.-based company broadened its strength in the space when it acquired Tei Biosciences and Tei Medical for $312 million. (See Medical Device Daily, June 30, 2015.)
By Mark McCarty, Regulatory Editor
WASHINGTON – Payers are quite interested in technologies that determine whether a patient really needs an expensive treatment, but fractional flow reserve (FFR) might have to take a back seat to instantaneous wave-free ratio (iFR) for determining the need to revascularize the coronary arteries, according to two presentations at ACC 2017.
Among the companies whose fortunes might be affected by any conclusions drawn from these studies is Heartflow, which reported at the 2016 edition of the American College of Cardiology annual meeting that it had wrapped up a study intended to nudge payers off the sidelines regarding the FFRct system. Heartflow's chief medical officer, Campbell Rogers, told Medical Device Daily that the company's cloud-based software, which employs CT imaging as source data, deferred invasive imaging for nearly a third of patients with no adverse clinical events at one year as a consequence of the deferral. (See Medical Device Daily, April 6, 2016.)
Justin Davies of Imperial College London said iFR avoids the need for adenosine used in FFR as a vasodilator, adding that the Define Flair study randomized the nearly 2,500 patients across almost 50 centers evenly to iFR and FFR. iFR also requires the insertion of a catheter to insert a pressure sensor wire to capture blood flow data, but the avoidance of adenosine sidesteps some serious, albeit rare side effects, depending on the route of administration.
"In total, more patients were deferred in the iFR arm," Davies said, noting that the 652 deferrals in the iFR arm constituted 53 percent of that group, while the 583 deferrals in the FFR arm accounted for only 47 percent of that side of the study. Bypass was performed on 25 patients in the iFR arm, compared to 42 in the FFR arm, while percutaneous intervention was likewise lower in the iFR group (565 total to 625).
"All these numbers are statistically significant," Davies said, noting that the rate of major adverse cardiac events (MACE) was 6.79 on the study article and 7.01 among controls, which Davies remarked was sufficient to demonstrate non-inferiority.
Define Flair is "the largest randomized controlled trial to date" comparing iFR and FFR, Davies continued, noting that this comparison was "performed in a study population reflecting real-world clinical practice."
The Instantaneous Wave-Free Ratio versus Fractional Flow Reserve guided intervention (IFR-SWEDEHEART) study, which enrolled slightly more than 2,000 in three northern European nations, also appeared at ACC 2017. This study also randomized the enrollment roughly equally to iFR and FFR, and disclosed "significant" lesions of the coronary arteries in 29 percent of patients whereas FFR located lesions in 37 percent.
Both studies appeared in the New England Journal of Medicine, which featured an editorial by Deepak Bhatt of Brigham and Women's Hospital in Boston, who remarked that FFR has not attained widespread use despite "strong data in its favor."
Bhatt noted that clinicians are wary of the risk that adenosine might trigger heart block or bradycardia, but patient discomfort and increased treatment times are also a factor (Davies said iFR shaves nearly five minutes off the 45 minutes ordinarily incurred in FFR).
Bhatt concluded that these two studies are not applicable to patients with acute coronary syndrome, but said that while FFR "has been the evidence-based standard for invasive evaluation of such lesions . . . it now appears that iFR may be the new standard."
TAVR LEAFLET THROMBOSIS RESURFACES
Two registry studies dealing with leaflet thrombosis for both transcatheter and surgical aortic valve replacements found their way to the dais at ACC 2017, the Savory and Resolve registries.
Raj Makkar of Cedars Sinai Medical Center in Los Angeles said subclinical leaflet thrombosis has up to now been reported as occurring at between 10 and 15 percent of transcatheter aortic valve replacement (TAVR) cases, although surgical aortic valve replacement (SAVR) is not immune to this problem. The two registries covered more than 930 patients total, more than two thirds of which were in the Cedars' Resolve registry. There was a large difference in mean time to CT, with 58 days elapsing on average for the TAVR enrollees, while the delay for SAVR patients was on average more than 160 days.
Reduced leaflet motion was defined in both registries as a restriction of motion of at least 50 percent, and about 13 percent of the TAVR patients were diagnosed with reduced motion, while the same could be said of only 3.4 percent of the SAVR patients. Reduced motion was actually associated with a lower rate of death in the two studies, although the rate of stroke/transient ischemic attack was significantly higher in the presence of this condition, 3.4 percent for normal leaflet motion compared to 10.4 percent for reduced motion.
The validity of these studies is hampered of course by their observational nature, but Makkar also acknowledged that the longer delay to CT for the SAVR group "makes it difficult to state leaflet thrombosis as the definitive cause" for stroke and TIA. And although the study was not sufficiently populated to contrast the rates of subclinical thrombosis across TAVR types, the Medtronic plc Corevalve incurred the nominally lowest rate at six percent, less than half the rate seen in the Sapien units by Edwards Lifesciences Corp.
By Mark McCarty, Regulatory Editor
WASHINGTON – The FDA broke an embargoed release of data for Abbott Laboratories' Absorb GT1 scaffold, advising clinicians that the rates of major adverse cardiac events in a large study were higher than seen with the comparator, but leading cardiologists at ACC 2017 were nonetheless unwilling to recommend that clinicians abandon the device.
The FDA's safety alert preceded the embargo placed on the news from the Absorb III study – sponsored by the Abbott Park, Ill.-based company – by nearly 50 minutes, but contained no information that was not included in the presentation by Stephen Ellis, one of the investigators in Absorb III. Ellis reminded that the primary non-inferiority endpoint for Absorb III in regulatory terms was based on one-year data, and that the company had hoped to keep data from years two through five under wraps until those data could be blended with Absorb IV data for longer-term assessment of target-lesion failure (TLF).
However, Ellis said the superiority of the GT1 over the Xience drug-eluting stent for TLF would not likely emerge until after the GT1 scaffold had absorbed, which is typically expected to occur at three years post-implant. Consequently, the company and FDA have agreed, after consulting with clinical investigators, to use years three through seven to test the TLF superiority endpoint, thus allowing the unblinding of data for ACC 2017.
Abbott has two-year data from Absorb III for roughly 98 percent of the nearly 2,000 patients in both arms of the study, and Ellis pointed out that the study article had met the non-inferiority endpoint for TLF at one year. As has been previously described, clinicians have been cautioned about implanting the device in patients with reference vessel diameters smaller than 2.5 millimeters, a predicament that colored the latest release of data.
The Absorb had a difficult time keeping up with the Xience for target-lesion failure for the 13-to-25 month interval (the actual period of elapsed time used for the nominal one- and two-year data collection set points), which occurred in 3.7 percent of all enrollees on the study article regardless of lesion size, while only 2.5 percent of Xience patients experienced TLF. After dividing the data by RVD as assessed by quantitative coronary angiography with vessel diameter of 2.25 milimeters as the threshold, the GT1's rate of TLF dropped to 3.2 percent in the larger set of vessels, but Xience also benefitted from this analysis, with only 1.9 percent experiencing TLF. More than eight in 10 of enrollees in both arms had RVDs in excess of 2.25 mm, according to Ellis.
At 25 months, the difference in TLF for the two arms for the entire study population had widened in absolute terms (11 percent for GT1 to 7.9 percent for Xience), as was the case for the subset with larger vessels (9.4 percent to 7.0 percent). However, the relative differences in TLF had actually narrowed.
Ellis said the generalizability of Absorb III is limited by inclusion of those with stable ischemic disease, and that the study is underpowered to evaluate low-frequency events. "Importantly, implantation technique was still evolving" as the study commenced with enrollment, he said, adding that the combination of predilatation of the vessel, appropriate vessel size selection, and postdilatation – an approach known colloquially as PSP – might go a long way toward resolving some of the differences between the two devices.
Antonio Colombo of New York Presbyterian said of the new Absorb III data, "I think you can look at the glass [as] half empty or half full." Colombo stated further, "with the proper technique and selection, you can make it non-inferior" to Xience, suggesting that if clinicians stay in bounds on vessel size, frequently invoke postdilatation with a noncompliant balloon inflated to at least 18 atmospheres, and routinely use intravascular ultrasound (IVUS) to guide the implant procedure, the device's performance should shape up well in contrast to the Xience.
Roxana Mehran of Mt. Sinai Hospital in New York said she was "somewhat comforted that the event rates are not extremely high" for the GT1, but that the data leave her "waiting for the promise of the future; superiority of this device" over Xience for TLF.
Mehran said the question of whether a patient with the GT1 should stay on dual antiplatelet therapy until the scaffold disappears is still unanswered. She said most of the patients in the study were not treated via the PSP protocol, and that it is not entirely clear how IVUS influences outcomes.
Ellis responded, "I think, based on these results, as long as you follow the inclusion criteria in Absorb III" and deploy the device in a technically appropriate fashion, "the results are similar to what you see in Xience." Nonetheless, he said, clinicians "should be up front with the patient" about the uncertainty.
Regarding the broken embargo, the FDA told Medical Device Daily that it has "interacted with Abbott to ensure it has the most up-to-date information on which to base its recommendations. As new information becomes available, the FDA will update its communications and recommendations as necessary."
By Mark McCarty, Regulatory Editor
The TAVR wars heated significantly at the annual meeting of the American College of Cardiology, where a new set of data for the Corevalve series of devices demonstrated that the Dublin-based Medtronic plc offering beats surgical aortic valve replacement on several scores for intermediate-risk patients, a population already served by a TAVR offering from Edwards Lifesciences Corp. of Irvine, Calif.
The 17th annual scientific sessions held by the American College of Cardiology commenced with the usual late-breaking clinical trial data releases, with the data from Surtavi serving as the premier device study presented on day one. Michael Reardon, a principal investigator in the 1,764-enrollee study, reminded that the study was conducted across more than seven dozen sites in the U.S., Canada and Europe. Numerically speaking, the Medtronic units outperformed surgical aortic valve replacement (SAVR) handily in terms of the primary endpoint of all-cause death and stroke (12.6 percent for TAVR and 14 percent for SAVR) at two years, but this measure failed to hit the benchmark for demonstrating superiority for the study article, although the Corevalve units' performance sufficed to hit the non-inferiority standard.
Despite the sheer volume of enrollment, Surtavi was a Bayesian trial that was principally populated by the legacy Corevalve in the device arm, while the successor, the Evolut R, accounted for 16 percent of the total TAVR devices used in the study. Operators handling the SAVR cases were allowed their pick of available surgical valve offerings in an effort to mirror real-world outcomes, which Surtavi replicated at least in one characteristic: Nearly one in four on the study article needed a pacemaker in this study, similar to a figure seen in a previous study of Medtronic valves in high-risk patients. (See Medical Device Daily, March 18, 2015.)
The enrollees, who on average were nearly 80 years of age in both the roughly numerically equal arms, were all in the range of 4.4 to 4.5 on the risk scoring system devised by the Society of Thoracic Surgeons. The TAVR arm included some patients who underwent percutaneous intervention for the coronary arteries while some of the SAVR patients also underwent bypass surgery, and one of the inclusion criteria was that the patient be in at least stage II heart failure.
Reardon, who had presented two-year Corevalve data for high-risk patients at ACC 2015, said the original enrollment had been winnowed to 1,660 by the time it came to attempt device placement. He said the 24-month data for all-cause mortality and disabling stroke presented "a very robust statistic for non-inferiority." The all-cause death at 30 days favored SAVR, which was 1.7 percent while TAVR's 30-day mortality was 2.2 percent. Of the SAVR figure, Reardon said "this is extraordinarily good surgery." The numbers flipped by two years, however, with TAVR all-cause mortality at 11.4 percent while SAVR yielded 11.6 percent. "TAVR stood toe-to-toe with surgery" and won on all-cause death at two years, Reardon emphasized.
Reardon remarked that this is the third consecutive study showing TAVR imposes a lower rate of stroke than SAVR, but he said the data do little to answer the question of whether hemodynamic performance is particularly important. Reardon said he was "very taken aback," by the persistence of the pacing problem, which he said will greatly affect patients who have a considerable life expectancy in front of them. "I think this is an engineering ... and site placement thing," Reardon continued, although he added that the ability to retrieve and re-place the Medtronic units gives the operator more breathing room to ensure proper device placement.
Among the other encouraging signs to come out of Surtavi is that the Medtronic devices imposed a stroke rate of 2.6 percent at two years, only slightly more than half the stroke rate of 4.5 percent of the SAVR arm. One of the confounders on the point of pacemaker in Surtavi was that the rates between Corevalve and the Evolut R iteration were very similar (25.5 percent for the legacy device and 26.7 percent for the newer edition), although the fact that the Evolut R made up only about one in six of the TAVR devices in this study complicates efforts to draw any conclusions on that point.
Reardon told Medical Device Daily that it can be difficult for less experienced operators to avoid placing a TAVR device without interfering with the function of the atrioventricular node, a predicament incurred when the device is positioned in such a manner as to impinge upon the outflow tract. Overcompensating for this hazard with the original Corevalve could lead to some problems with obtaining a proper fit of the device into the aortic annulus, he said.
Reardon said the clinical discussion for device selection revolves around several factors.
"We look at things such as whether there's a lot of calcium in the outflow tract," he said, noting that a self-expanding device is perhaps a better bet to avoid rupturing the annulus, which could prove lethal. On the other hand, he said, a practitioner might go to a balloon-expandable unit if the width of the aortic sinus exceeds a certain benchmark, although most of the variability in sinus width is indifferent to device type. Reardon said the ability to reposition the Medtronic offering is really the best argument for the Evolut R.
When asked about private payers, Reardon said, "most of them have been willing to cover [TAVR] in the high-risk group," although they are obviously less inclined at present to cover these devices for intermediate-risk patients. "The bigger problem is not the payer," Reardon said, explaining that a hospital's chief financial officer will say that SAVR "has one of the highest contribution margins in the hospital, and you want to replace it with a TAVR, which barely has a contribution margin." As for the patients, "they all want TAVR," Reardon shrugged.
The Evolut Pro is scheduled to debut at ACC 2017 on March 18, and Reardon said the device "has an external skirt to cut down on paravalvular leak. Stay tuned, it's going to move things forward," he advised.
TAVR WARS HEATING UP AGAIN
The competitive temperature was on display on March 17, as demonstrated by the full-page ad taken out by Edwards for its Sapien 3 TAVR device in the ACC.17 Daily, the circular published by the college each day during the ACC's annual scientific sessions. The Edwards advertisement bragged that the company currently has the only TAVR offerings approved by the FDA for use in intermediate-risk patients, although the numbers from Surtavi suggest Edwards will lay sole claim to that population for only a little while longer.
Larry Biegelsen of Wells Fargo of San Francisco said in an investor's note that the data from Surtavi should prod the FDA to expand the device's indications to intermediate-risk patients. Biegelsen pointed out that SAVR performed substantially better on the primary endpoint in this study than was anticipated, mostly because of a lower mortality rate than has been seen in other studies, such as Partner 2A, a study of the Edwards Sapien XT and Sapien 3.
Biegelsen noted that Edwards may argue that the data for the Sapien 3 device as seen in Partner 2A bested the Surtavi data for Corevalve units in terms of moderate to severe paravalvular leak and rate of pacemaker implant, but that Medtronic can resort to the assertion that those Sapien 3 data were drawn from an observational study that employed propensity matching to filter out bias. The problem for Medtronic with the Evolut R iteration is that the pacemaker rate was roughly double that of the Sapien 3 (nearly 26 percent versus 12.4 percent on the Sapien 3), and the rate of paravalvular leak was nearly triple for the Medtronic items against the Sapien 3. Still, Biegelsen observed, Medtronic has the Evolut Pro waiting in the wings, a device Medtronic is expected to bring to market later this year.
An investor note from Rick Wise at Stifel Financial Corp. of St. Louis, characterized Reardon's presentation as positive for both Medtronic and Edwards because the data "argue for continued, steady TAVR adoption" for intermediate-risk patients in the coming years. Wise commented that the Surtavi data might have been more persuasive had the entirety of the device arm had been populated by the Evolut R.
"Any lingering hesitancy about referring potential patients [for TAVR] should gradually diminish," Wise said, noting that the comparative stroke rate at 24 months was 2.6 percent for the TAVR units and 4.5 percent for the surgical arm. He said Medtronic has already forwarded the Surtavi data on to the FDA, stating that the approval process "would likely take three to six months." He rated Medtronic's shares a hold with a target price of $84.
[caption id="attachment_5283" align="alignleft" width="300"]We believe we've found your cardiologist.[/caption]
The news at ACC 2017 has varied by product type, including TAVR devices, coronary artery stents and imaging modalities, As usual, there are potential and verifiable winners and losers, and in some cases, companies playing catch-up with the competition in an effort to take the lead, but this meeting is never boring.
FDA says ‘what embargo?’
In one of the more interesting stories at ACC 2017, the FDA broke an embargo regarding 25-month data for the Absorb GT1 coronary artery scaffold by Abbott Vascular. The agency advised clinicians of the higher-than-expected rates of major adverse cardiac events seen in the new data set from Absorb III, but two leading clinicians indicated they are not ready to jump ship on the GT1.
Antonio Colombo said he sees the glass as half full and half empty where the GT1 is concerned, and recommended that operators stick with the guidelines where pre- and post-dilatation are concerned, although he also recommended the use of intravascular ultrasound. Roxana Mehran was less forgiving of the news, but indicated no explicit aversion to the GT1 until a better unit arrives. The bottom line seems to be that operators need to tighten things up for their patients who want a device that isn’t a device after 36 months.
‘Instant’ improvement over FFR alleged
Can functional flow reserve (FFR) be bested by instant wave-free ratio (iFR) for determining whether a patient ought to undergo some sort of treatment for coronary artery disease? That’s a question taken up by two studies appearing at ACC 2017, including the Define Flair study, which set out to demonstrate the non-inferiority of iFR for MACE (a composite of death, MI and unplanned revascularization) compared to FFR.
Define Flair suggested that iFR led to fewer PCI and bypass procedures, and this approach eliminates the need for adenosine to boost blood flow, a necessity in FFR. Another advantage is that it shaves about four minutes off procedure time compared to FFR, which might not seem like much, but which might get hospital administrators at high-volume sites off the fence if the up-front cost isn’t too dear.
It’s a no-brainer that payers are sure to respond if iFR can keep up with FFR in terms of outcomes and beat FFR in terms of cost, and any perception that iFR eliminates needless revascularization would clinch the deal outright. A win for iFR would be a big win for Volcano Corp. and its new parent company, Philips.
Medtronic ‘skirts’ the PVL problem
Just take your latest transcatheter aortic valve device and slap a wrap around the bottom, and what do you get? A skirt that tamps down on paravalvular leak, or so that’s the message from Medtronic, which released 30-day data for the Evolut Pro device, a design based entirely on the Evolut R with the exception of the “skirt.”
Medtronic has worked for some time to make the basic Corevalve retrievable so operators can reposition the device, a boon for less experienced operators. This is a preliminary study, but there were no incidents of moderate or severe leakage at 30 days in any of the 60-some odd enrollees, a big improvement over 30-day data for the Evolut R. More than one in three of the devices used in this study were repositioned, and pacemaker rates were down sharply compared to Evolut R.
For the regulatory geeks in the crowd, the question here is whether the FDA sees this as a PMA supplement or a traditional PMA. There seems to be some thought that the FDA will decide on this device in the near term – before the end of the year, perhaps – which sounds like a PMA supplement because that is nowhere near enough time for a pivotal study. And before we dismiss this as non-news, let’s remember that Jeff Popma of Beth Israel Deaconess called out the FDA in a public forum two years ago (almost to the day, as a matter of fact) on the question of whether a pivotal clinical trial mandate is really justified for a modestly modified PMA device.
Popma had argued that 30-day data for Edwards Lifesciences’ Sapien 3 foreclosed the need for a new clinical trial, a position that might seem to be taking root at the FDA. The event in question? Why, ACC 2015, of course. Just look up the March 18, 2015, issue of Medical Device Daily to see for yourself.
The FDA issued a Medwatch alert on March 18, regarding the rate of major adverse cardiac events for the Absorb GT1 scaffold by Abbott Vascular, breaking an embargo placed on the news at the American College of Cardiology annual meeting. The agency noted that the two-year data from the Absorb III study demonstrated an adverse event rate of 11 percent for the composite endpoint of cardiac death, heart attack or revascularization, a substantially higher rate than seen in the comparator arm of the study, which used the company’s Xience drug-eluting stent, which demonstrated a rate of 7.9 percent for this measure.
The FDA further noted that the rate of thrombus development on the GT1 was 1.9 percent (compared to 0.8 on the Xience) and said the problem was more pronounced in smaller vessels. Abbott was set to present these data at ACC 2016 with an embargo time of 10:45 a.m. U.S. Eastern time, while the FDA statement went out more than 45 minutes earlier. Abbott noted that the FDA guidance regarding the use of the GT1 in smaller vessels arrived after the study had enrolled, and after the implant technique guidance for the device had been updated.
Medical Device Daily will cover this story in greater detail in an upcoming issue.
By Stacy Lawrence, Staff Writer
Corporate restart Renalguard Solutions Inc. has raised a $14.5 million series A round to get its device through an ongoing U.S. pivotal trial to protect against contrast-induced acute kidney injury and onto the market. Renalguard is designed to measure patient urine output in real-time and then to match that amount to hydration introduced during catheterization procedures.
The Milford, Mass.-based company aims to have pivotal data in early 2018, which could be followed later next year by a PMA approval from the FDA. The financing will also go to support development of the device in additional indications as well as to back marketing in Europe, where it has had a broad CE mark since 2008 for balancing patient fluids for up to 14 days.
CLEARING OUT CONTRAST
The technology behind Renalguard comes out of medical device industry incubator Coridea, run by industry gurus Mark Gelfand and Howard Levin, who have been behind a number of industry success stories including Ardian Inc. and Respicardia Inc.
An estimated 10 percent to 20 percent of patients who undergo cardiovascular diagnostic and interventional procedures are at-risk of developing contrast-induced nephropathy (CIN). This is an acute form of kidney injury resulting from damage caused by the exposure of kidneys to the dye itself.
Renalguard works by synchronizing the measurements of a urine collection set with the operation of a hydration fusion set. The idea is to match patient output to the milliliter in real-time. This is expected to produce higher urine rates than standard diuretics alone, thereby helping to protect the kidneys.
"Contrast is very good at what it does, which is stopping x-ray. If you can get patients urinating, you can flush those toxins out and let the kidney rest," observed Renalguard President Andrew Halpert in an interview with Medical Device Daily. But he cautioned that simply increasing hydration, as well as under-hydration, during catheterization procedures both lead to less urine output and can result in increased acute kidney injury.
Either under- or over-hydration via standard infusion can lower urine rates, increasing kidney exposure to the toxic contrast agent. With an increase in the rate at which contrast is expelled, this is expected to reduce the oxidative stress on nephrons within the kidney, making them less susceptible to damage.
Post-procedure kidney damage is a key predictor of patient outcomes, as well, so preventing that may actually help to improve success rates of cardiac catheterization procedures.
PUT TO THE TEST
Renalguard has been in a series of European trials comparing it to various standard-of-care approaches as well as examining outcomes. One found results with the system to be superior to overnight hydration, while another found it was better than sodium bicarbonate hydration.
In terms of patient outcomes, a trial resulted in a significant reduction in post-procedural acute kidney injury following transcatheter aortic valve replacement (TAVR). Finally, another found significant improvement in long-term outcomes for patients versus standard therapy.
The CIN-RG adaptive-design pivotal trial is underway in the U.S. It will enroll at least 326 patients and up to 652 patients, depending upon a sample size re-estimation after the study hits a threshold of 163 patients. It is being randomized 1:1 to standard-of-care or Renalguard treatment, with a primary outcome measure of incidence of contrast induced nephropathy within 72 hours.
There are a number of standard-of-care approaches physicians can use to try to moderate the detrimental effects of contrast on the kidneys. They can hydrate the patient, use diuretics to induce urination and try to limit the volume of contrast used.
Halpert noted that Renalguard already has about 1,500 patients worth of data out of Europe, so on the U.S. pivotal trial front he's "very optimistic about what our results will look like."
FROM RESTRUCTURING TO COMMERCIAL STRATEGY
The company that became Renalguard has a decades-long history that stretches back to a founding in the 1980s and winds through a couple of medical device technologies and a time as a public company.
It was refocused specifically on kidney protection in 2004 and then taken private in 2014. Lien holder Genesis Capital, which had helped fund the public iteration, continued to support it in this series A round.
The new financing was led by Exigent Capital with participation by Genesis and other private equity investors. Alan Adler, former CEO and chairman of Oridion Medical, has joined the Renalguard board to represent Exigent.
"Acute kidney injury (AKI) caused by cardiac interventional procedures is a serious and costly health care problem that is not currently remedied by any viable solution," said Adler.
He continued, "After spending much time extensively reviewing the published clinical data related to Renalguard therapy and speaking with leading clinical practitioners who have become dedicated users of this technology, I am convinced that Renalguard has the potential to become the standard-of-care for significantly reducing the incidence of AKI in the huge number of patients undergoing these procedures."
Renalguard already is commercializing on its own in Europe, where it is getting particularly strong uptake in Germany and Italy, Halpert said. The company could do so in the U.S. as well, assuming an FDA approval, but a partnership would bring more value to the table.
"I want to see this used in every catheterization patient around the world that's at-risk; the value proposition is obvious," he said. He sees the ideal potential strategic partner as one that already has catheterization lab products, particularly those who could benefit broadly with a systematic means to improve outcomes in procedures such as TAVR.
"This is not a me-too device, it takes a sales force that can speak to physiology. But there could also be a massive economic benefit as we move to value-based payments," said Halpert. "Cath labs are becoming much more concerned with 'what's our rate of complications and how is that going to impact our payments?'"
He concluded, "Renalguard is the only thing that's been shown to reduce the incidence of acute kidney injury, and it can improve patient outcomes."
By Stacy Lawrence, Staff Writer
Medtronic plc has received the first FDA approval for a transcatheter pulmonary valve to treat patients whose bioprosthetic pulmonary heart valves have failed. For these congenital heart disease patients, many of whom undergo repeat open heart surgeries as children and into adulthood, this validates the use of the Melody Transcatheter Pulmonary Valve (TPV) to avoid additional surgical procedures.
BEYOND OFF-LABEL USE
The Melody TPV has long been used off-label in this indication, but a retrospective study underlying the approval found that it's effective even in pediatric and adult patients with a smaller valve. It is an artificial heart valve made from the jugular vein valve of a cow that is sewn into a small metal frame. It's inserted via a catheter threaded through a small incision typically in the groin and placed while the heart is beating.
It was FDA approved in 2015 for congenital heart disease patients with a dysfunctional right ventricular outflow tract conduit, which is an animal- or cadaver-based graft with a valve inside that connects the heart to the lungs. Prior to that it was available under a Humanitarian Device Exemption from the FDA that dates back to 2010. The Melody TPV won a CE mark in 2006 to treat patients with failing pulmonary valve conduits.
"All bioprosthetic valves, catheter-placed or surgically placed, will likely undergo some deterioration, although they do provide a fairly long-term solution," Mayo Clinic pediatric cardiologist Allison Cabalka, who was the principal investigator on a retrospective study of bioprosthetic valve replacement, told Medical Device Daily.
"The patient would have had a surgically placed tissue valve and when that valve undergoes deterioration, which can be in a few years to 10 years after the valve is placed, they have the option of transcatheter placement," she said.
BUYING TIME WITH A TPV
During a bioprosthetic valve replacement procedure, the Melody TPV is placed within the existing, older bioprosthetic valve, pushing it to the side rather than attempting to retrieve it. The nonfunctioning bioprosthetic valve is left in place and provides a "fairly nice framework to support the Melody valve," said Cabalka.
The Melody TPV has been used in more than 10,500 patients worldwide. Patients in the original IDE study for Melody TPV are being followed for 10 years, ending in January 2020. The initial results at five years showed that 91.7 percent of patients were free from conduit reoperation.
In the new indication, an estimated 5 percent of congenital heart disease patients – whose bioprosthetic pulmonary heart valves have failed – are eligible for the Melody TPV or other transcatheter options.
Cabalka headed a 10-center retrospective study of Melody TPV use in bioprosthetic valves, which she said found that it "works very well in both pediatric and adult valves." She noted that the procedure requires only a one-night hospital stay with the obviation of open heart surgery.
"The idea of catheter-based surgery is to extend the life of the valve; it is very important to avoid complications from repeated open heart surgery," she said. "If we didn't have a catheter-based option to treat bioprosthetic valve failure, then they would have to undergo surgery. They will typically suffer ventricular dysfunction in the right ventricle, the tricuspid valve may also fail."
Continued Cabalka, "Waiting, in terms of preserving overall heart function for years, is not a good option. Functionally speaking, the only other option is open heart surgery."
GOING SMALLER AND BIGGER
Even though off-label use was common, she expects that the FDA approval could help bolster use in smaller patients that were previously a particular concern. "I suspect that there may be more use of the Melody valve or other transcatheter solutions, especially in younger patients with a smaller valve or adult patients with a smaller valve," she said.
"We have seen in our analysis that valve function is very good. Before, there may have been concerns that it would be limiting in terms of hemodynamics," concluded Cabalka.
She added that the use of Melody TPV could also prove useful as a repeat procedure, depending on the nature of the valve the system is implanted into. That could provide these patients more options to avoid open heart surgery and associated complications.
For small children who see more stenosis, or narrowing, as they become adults, Cabalka envisions that they could undergo open heart surgery – thereby laying the foundation for transcatheter procedures for the rest of their lives.
Beyond the Melody TPV in congenital heart valve development, Dublin-based Medtronic is also in the midst of a pivotal trial for the Harmony TPV. It is an investigational transcatheter pulmonary valve designed for the roughly 80 percent of patients whose initial procedure is insufficient to open up their right ventricular outflow tract (RVOT). The expectation is that the Harmony TPV will be an alternative to open heart surgery for these pediatric and adult patients.
By Mark McCarty, Regulatory Editor
The regulatory law firm of Epstein Becker Green (EBG) has petitioned the FDA to set a limit to the number of days the agency can take to review petitions regarding combo product designations, stating that as matters stand, the agency is "unaccountable for egregious delays in decision-making."
The combination products dilemma has roiled relations between the FDA and regulated industries for some time, and the EBG petition, filed on behalf of the Combination Products Coalition, highlights yet another source of tension. Most of the controversy up to now has revolved around the process by which the Office of Combination Products determines a combo product's primary mode of action, but the EBG petition alleges that "there is at least one appeal which has been 'under consideration' by FDA for 18 months and counting."
EBG's James Boiani, the author of the letter to the FDA, argued that in the absence of some mechanism of accountability, the FDA "cannot be counted on to act" to address the delays of these appeals regarding designation. Boiani remarked that the appeals process would likely require little or no more than the 15 maximum pages of documentation allowed for a request for designation, and suggested the agency invoke a deadline of 60 days to review an appeal for an unfavorable request of designation.
Boiani said inaction on the agency's part may "thwart implementation of process changes" to the agency's determination of primary mode of action (PMOA) as seen in the 21st Century Cures legislation. The petition further requested that the FDA handle any appeals filed before Oct. 1, 2016, by March 9.
Boiani told Medical Device Daily that this petition was driven in part by a matter he is handling for a client, but he added, "I don't think it's a volume issue." He said the petition may land on the desk of an associate FDA commissioner for special medical products, but he said some of the delays on these appeals may be incurred by the agency's Office of Chief Counsel.
In any event, Boiani said the delays in dealing with these product designation appeals is "in part managerial, because there's no timeline" for responding to such appeals, in contrast to other types of appeals available at the agency. The Office of Combination Products might be bogged down due to a lack of responsiveness from the centers involved in these reviews, and Boiani noted that the lack of a deadline for these appeals stands in contrast to the deadlines for handling drug and device applications, and thus something from OCP is "pushed to the back of the pile over and over again."
Drug and device makers might be predisposed to using the citizen petition process in order to push the agency to respond, but Boiani noted that the citizen petition process eliminates a large area of confidentiality. "As problems like this arise, industry starts looking for creative ways to get some response from FDA," he shrugged. While Boiani's letter had requested that the agency fix the problem via rulemaking, he remarked that the FDA could handle this with a guidance, or "they could do a direct final rule, which would publish the regulation right away without comment" because it affects FDA only. Regardless of which approach the agency took, "anything that gets some guidelines would help," he said.
Boiani said he has discussed the predicament with some on Capitol Hill, and had several physicians write in to support the case he is handling for a client. "At some point, I may have to take them to court" for his client, he said, which would raise the profile of this question even further. The citizen's petition would also serve to "make it more public so others can weigh in about their experiences" as well, he said.
COMBO PRODUCTS ABOUND
The combo product predicament has affected more than just the Office of Combination Products, and seems to have had a suppressive effect on guidance development and on a number of requests made to the agency by drug and device makers. The implications are that it will take more than the discussion of primary mode of action (PMOA) seen in the 21st Century Cures bill to cure the FDA's difficulties with combination products.
One example of this is the January 2013 draft guidance for post-approval modifications made to a combo product, which drew five comments to the docket. The Combination Products Coalition said there seemed to be some differences between FDA staff and industry on the question of when a new submission is required for changes to a constituent part of that product.
Combo products were also cited in the March 2014 medical device classification rule, which would have made a device component a class III device in instances in which the associated new drug application or biologics license application was still pending. In addition, a search of Cortellis Regulatory Intelligence lists a draft guidance dated Jan. 17, 2017, dealing with human factors studies for drug-device combinations when submitted with a generic drug application. The Clarivate Analytics Cortellis database also pointed to the February 2016 draft guidance for human factors engineering studies for combo product design and development, which according to the listing at regulations.gov is not yet finalized.
Among the recent industry petitions regarding combination products was the Dec. 27, 2016, request by Mallinckrodt Pharmaceuticals of St. Louis, addressing the use of generic versions of Inomax (nitric oxide) and the Inomax DSir delivery system. Mallinckrodt said it had previously petitioned the agency on a similar matter in June 2016, but that the agency had issued a nonsubstantive denial due to the absence of a generic application for Inomax, and because of deadlines for response to such petitions said to be imposed by the statute under subsection 355 of Title 21 of the U.S. Code.