By Richie Crider
GAITHERSBURG, Maryland The FDA general and plastic surgery devices panel yielded a 6-4 vote that the benefits outweigh the risks associated with the TissuGlu internal surgical adhesive by Cohera Medical (Pittsburgh) in wound care closure. The application breezed through the vote on whether the data indicated the device is safe by 11-0, but the efficacy vote narrowly favored the device at 6-5. The tight benefit/risk vote was driven in part by what the panelists said was an overly broad indications as well as by what several panelists characterized as an inadequate pivotal trial design.
TissuGlu, which is delivered using a hand-held disposable delivery device containing 5 mL of the adhesive, is indicated for the approximation of tissue layers where subcutaneous dead space exists between tissue frames and large flap in surgical procedures, such as abdominalplasty. Typically, patients who undergo surgeries requiring large flap repair are fitted with drains or require aspirations post-surgery to remove fluid from seromas. During the public hearing portion of the meeting, former patients testified about the pain and discomfort of drains and fluid aspirations, with drains being the least preferred option. Caregivers, patient advocates and others also testified, providing explicit details of the pain, discomfort and anxiety patients experience with drains and slower recover times that result.
The sponsor conducted two clinical trials one to compare days to drain removal when using the glue vs. standard wound closure devices, such as sutures, and another to examine the non-inferiority using TissuGlu during standard wound care closure procedures with no drains. Both studies were conducted in weight loss and non-weight loss patients, such as those recovering from a mastectomy. In the first study, TissuGlu tended to decrease the time to drain removal with no significant difference in adverse events. In the second study, the results suggested the need for more postoperative fluid aspirations and higher rates of seromas in patients who had a history of weight loss.
But for the panel, uncertainty over the device's effectiveness and risks boiled down to study design. Panel member Alan Matarosso, a board certified plastic surgeon in New York City, abstained from voting on the final question because the sponsor failed to capture whether patients prefer drains to aspirations. Panel chair Frank Lewis of the American Board of Surgery (Philadelphia), said the sponsors should have conducted a superiority trial in comparing the device to standard wound care devices for the indication.
Hobart Harris, chief of general surgery at the University of California San Francisco (San Francisco), who voted no on the efficacy question, said he felt the second trial "was not well designed and did not lead to a positive conclusion." Murad Alam, professor of dermatology at Northwestern University's Feinberg School of Medicine (Evanston, Illinois), also voted no to the question for the same reason.
"I also felt that the info was limited," Alam said. "I really wanted to like this product. It is the first in vivo strong glue, and I can see anecdotal information that it works . . . but based on the best data that was available to us, I didn't feel like I was confident based on that data."
In response to panel concerns that the device was not tested to determine if the glue could be used without a drain, the sponsor pointed to trial data showing 73% of patients did not require a drain. However, 27% of those patients required additional post-surgery treatment for seromas, such as fluid aspirations. Therefore, the panel pressed the sponsor as to why neither study had an arm to test whether the glue is more effective and less risky than standard wound care devices when used without drains.
Peter Rubin, chair of the department of plastic surgery at the University of Pittsburgh (Pittsburgh), testifying on behalf of the sponsor, said it would have been hard to design such a trial, get people enrolled and receive approval from the institutional review board. "That would be perfect but problematic," Rubin said. "If we can't get patients, even though it's the best trial design, you can't do it."
In response, the panel told the sponsor that a more clearly defined trial endpoint, one that would have let physicians know when to intervene in a seroma or when to let it resolve on its own, would have been ideal. The panel then asked Joe Michaels, a plastic surgeon at Johns Hopkins Hospital (Baltimore) the study site where the most aspirations were performed if he believed the use of the glue in absence of drains results in better patient outcomes as it relates to safety and effectiveness.
"I'm not aware of any surgeon for abdominalplasty or doctors performing this without drains so drains are a standard of care so not placing a drain is unethical," Michaels said. "Based on data, I don't think it's ethical to compare the groups at this stage." The panel asked other physicians involved with the trials if they thought TissuGlu was superior to using drains. Sheri Slezak, chair of plastic surgery at the University of Maryland (College Park, Maryland), praised the device, saying the glue could lead to the reduced use of drains.
"There is evidence that it is in selective abdominalplasty," Slezak said. "I think [where it is] superior is in regard to patient comfort. You could use any [device], but patient would prefer not to have a drain from a comfort standpoint." However, the panel continued to press the sponsor on trial design. In the end, the chair said he "finds it odd that the trial, which would have shown the product to be the most effective, was not done."
Patrick Daly, president\CEO of Cohera Medical, took the panel's criticism of the trial designs in stride, saying he anticipated a thorough and somewhat rough review because the product is so novel.
"We are extremely pleased with not only the outcome but also the input from the panel, and we are already looking forward to working with the FDA to get this on the market," Daly said. I think the reason the panel gave us some harsh feedback and critical feedback is because when you are the first one out in the snow, you have to cut your own path, and that's what we've done here . . . I think we saw some trepidation and some concern, but at the end of the day the data won out."
Published August 5, 2014