- While urogynecologists need to be more judicious in selecting patients for surgery and informing of adverse event risk, well-trained doctors should still offer women with pelvic organ prolapse the full range of treatment options — including transvaginal mesh implanted in the anterior vaginal compartment — particularly in cases where a woman is not a good candidate for native tissue repair, FDA's obstetrics and gynecology devices panel suggested Tuesday.
- That line of thinking may leave room in the space for Boston Scientific and Coloplast, the two remaining companies with transvaginal mesh products for sale to treat POP. Both have premarket applications under review by FDA, a requirement since the agency moved the devices into Class III in 2016.
- Still, panelists and other public speakers questioned how FDA will be able to confidently determine a benefit/risk profile for the products based on data from postmarket surveillance studies, also known as 522 studies, which FDA mandated to manufacturers in 2012. At the time, FDA told companies the studies could also be adapted to support possible future PMA applications.
It wasn't your typical FDA advisory committee meeting: The expert advisers to the agency did not vote on specific questions, instead using them as a jumping off point for discussion.
Most panelists agreed that more extensive, randomized data, as well as a heavy emphasis on subjective, quality-of-life outcomes are key to establishing safety, efficacy and an overall superior or non-inferior risk/benefit profile of the devices. But how to realistically gather that data and make timely decisions remains at issue.
Among the expert group's consensus recommendations:
- Future PMA studies ought to follow patients for at least 18 to 24 months, while postmarket studies should last at least five years.
- Transvaginal mesh procedures should prove superior to native tissue repair at 12, 24 and 36 months when considering use for the general population of women, but simply prove non-inferior at those time points in cases of women who have failed native tissue repair or are otherwise not appropriate candidates for that procedure.
- Quality of life or subjective outcomes should be given heavy importance in considering patient success, given that POP is a non-life threatening condition; and women should be advised to not expect their implants to be durable beyond 10 years.
Since the panel last convened to discuss the mesh in 2011 and FDA subsequently ordered postmarket surveillance studies, all but two companies left the market and the devices were moved from Class II up to Class III. Clinical trials expert Rick Chappell, who also participated in the 2011 advisory panel, said he felt he owed it to the patients who testified in 2011 to "not be here in another eight years."
Chappell was among the majority of panelists in favor of longer studies. But many others noted research challenges, including long-term patient retention and the fact that surgeons involved in research tend to be better trained and more experienced, leading to higher patient success rates than are found in the general population. Ben Fisher, director of FDA's reproductive, gastro-renal, and urological devices division, also reminded panelists that while a 10-year study sounds ideal, such lengthy research does not balance the agency's need to make timely regulatory decisions for patients.
The discussion came in light of data released by FDA last week showing that between January 2008 and October 2018, the agency found 10,391 Medical Device Reports citing serious injury, 806 citing device malfunction, and 77 citing death related to POP mesh products. However, those figures could be much lower than the actual scope of complaints, said Madris Tomes, a former UDI external program manager at FDA who now analyzes adverse event data through her company Device Events.
In a presentation, she showed how features of FDA's Manufacturer and User Facility Device Experience database enable manufacturers to code reports in a way that disassociates harm from a device problem, and how summary reports that include complaints from many patients can be counted as a single adverse event case. Tomes' review of adverse event reports for POP mesh products as of Jan. 31, 2019 found 292 patient deaths.
“I’m going to openly admit that the MDR reporting system is not a perfect one," Fisher later said.
Manufacturers emphasized the differences in their PMA application products versus earlier products that had been studied. Though the panel was not tasked with considering specific products or product characteristics, Richard Morton, Boston Scientific's vice president of clinical sciences, reminded the experts that the company's Uphold Lite product in question was not the same as Uphold products formerly on the market, and Coloplast's Dale Klous, director of clinical science, highlighted that the company's product in question is the lightest-weight mesh ever available and features larger pore size than former designs.
Postmarket data in premarket applications
Panelists and patient advocates alike questioned how well the companies' 522 studies can serve the high bar for PMA-caliber studies. This round of PMAs is the only known instance of FDA allowing postmarket surveillance study data to suffice as PMA-supporting data, an agency spokesperson said.
Panelist Madeline Dick-Biascoechea asked professional society leaders whether the data collection currently in the works would be good enough for FDA to make a regulatory decision.
"Given that you all three agree that we don't have enough [stringent data] to make decisions, do you think completed 522s will give us the data we need given that they're not [randomized blinded controlled trials]?" she posed.
Some professional groups offered support, though not ringing endorsement, for the 522 data.
Society of Gynecologic Surgeons' Megan Schimpf noted that most data available involves dated devices and therefore 522 results will be the "best we've got for products that are out on the market right now," adding, "we regularly have to use less than pristine trials in gynecologic surgery."
American Urogynecologic Society's Geoffrey Cundiff said it was "premature to say if we can judge it based on 522 data," citing the fact that efficacy and complications could be different at the three-year mark and can continue to change over time.
Given consensus surrounding importance of quality-of-life measures, panelists recommended that physicians better gauge a baseline for patient symptoms pre-treatment and offer validated questionnaires that would ideally be standardized across the urogynecologic field. The group agreed that including a question a few years out from the procedure as to whether the patient would elect to have the procedure again would be useful.
At the end of the day, panelist and statistician Jason Connor expressed frustration with the lack of progress on how regulators and physicians are able to quantify risk to patients, saying that the big question still at hand is just how rare serious adverse events are for women with transvaginal mesh implants, a concern shared by some patient advocates.
"The panel's feedback, for the most part was, 'we want to see as much data as we can get, but we know it's hard to get,'" National Women's Health Network Executive Director Cindy Pearson told MedTech Dive. "We still don't know how to tell women how likely a devastating outcome will be ... how likely it is that your life is ruined, you wish you had never had it, you suffer every day. Is it one in 1,000? One in 10,000?"
"Nothing that happened today gets us closer to that," she said.
Oversight of women's health-specific devices will be in the spotlight again March 25-26 when FDA convenes its general and plastic surgery devices panel to discuss breast implants.