Tuesday, the FDA gathered patients, doctors and a panel of experts in Gaithersburg, Maryland to determine the future of the three remaining polypropylene mesh implants still on the market used to treat pelvic organ prolapse (POP).
POP mesh supports pelvic organs - the uterus, colon or bladder - that can fall through the vagina due to gravity or childbirth. POP mesh is larger than “slings” that hammock the urethra as a treatment for incontinence and it is connected to some of the most devastating life-altering complications that have led to the filing of more than 104,000 product liability lawsuits in the U.S.
POP mesh is considered a permanent implant.
Mesh complications include chronic infections and pain, mesh shrinkage, autoimmune reactions, nerve damage, and mesh erosion into organs, among other problems.
While the POP mesh placed next to the colon or posterior placement is off the market because of the complications, such as sepsis, the focus of this panel hearing was the three remaining POP meshes placed on the front of the vagina.
They include Boston Scientific’s Xenform (bovine dermis) and Uphold LITE, and Coloplast’s Restorelle DirectFix.
Uphold and Restorelle are made of the polymer polypropylene and promise larger pores to minimize the buildup of infection and scar plate formation, a problem with the previous generation of POP pelvic meshes.
(Smaller pore mesh for transvaginal placement to treat stress urinary incontinence continue to be the smaller pore less than 1 mm in size).
The challenge for Boston Scientific and Coloplast is how to have their meshes remain on the market with the least cost and effort.
Their PMA (premarket approval) applications are pending and within them, the mesh makers are attempting a never before tried approach to gain market share.
Back in 2012, the FDA required companies monitor the health of women implanted with mesh who were suffering complications. These 522 studies are a sort of an “after the fact” monitoring to make up for the lack of regulatory rigor imposed on manufacturers prior to selling the mesh. They are design by the mesh makers according to their own favorable criteria.
The 510(k) clearance process involves no clinical trials, just an exchange of paperwork and is used to clear more than 90% of medical devices for market.
Boston Scientific and Coloplast want to use these less rigorous 522 studies to keep their meshes on the market, something called a “novel approach” to approval by one panelist.
The FDA will not comment on when it will make a decision on the pending PMA applications but it generally follows the recommendations of any expert panel. The PMA applications are not made public unless or until the devices are approved.
The dozen or so patients and patient advocates testifying to the panel Tuesday morning were given five minutes each to testify during one hour. The rest of the day was taken up by the mesh industry, FDA representatives and panel discussion.
As many women report the emergency of autoimmune issues after their mesh implant, it was a setback to hear panelist Dr. Geoffrey Cundiff, the current president of AUGS and a uyrogynecologist from Canada, say those conditions will not be considered by the panel.
(Interestingly, Dr. Cundiff stated he had no conflicts of interest even though AUGS derives approximately half of its support from the medical device industry, according to its annual reports.)
Autoimmune issues including fibromyalgia, Lupus, rashes, and systemic reactions have been noted in a substantial number of women who have undergone a polypropylene mesh implant.
How many? No one knows because it is not being tracked.
So in discussing the safety and efficacy profile of the post approval monitoring, no autoimmune reactions were considered. Any patients with connective tissue disorders, or pre-existing autoimmune issues were eliminated from the 522 studies.
Among those testifying in opposition to the easier standard for mesh approval were lawyers, statisticians, patients and health advocates.
Kila Baldwin, of Kline Specter, a Philadelphia law firm that has won hundreds of millions of dollar for mesh-injured clients, said her firm has 3,000 current clients who have had mesh placed for anterior prolapse repair.
“The vagina unlike like the abdomen where hernia mesh had been used, has unique bacteria and peroxides that cause scarring and inflammation. The mesh stiffens causes retraction, loss of pelvic elasticity, organ dysfunction, erosions, and or pain.
“Unlike complications associated with the native tissue repairs, mesh complication are permanent. You can't undo retraction and scarring. The complications of transvaginal mesh used in the compartment far outweigh the stated benefit of less chance of recurrence.
“These complications have been well-known among mesh manufacturers, and the physicians who consult with those manufacturers for many years.”
She added that no mesh should be marketed until adequate long-term studies are conducted.
Patient Barbara Melling, who traveled from Oregon to the meeting, said her life has been destroyed by pelvic mesh and she recounted how at one time she had to void (urinate) using a bucket in her living room.
“Nobody is listening to us!” she said visibly upset.
Michael Carome with Public Citizen filed a petition in 2011 to have nonabsorbable surgical mesh for POP pulled from the market. Three years later, in 2014, the FDA denied the petition, despite the fact that in 2011 the agency determined mesh injures from POP mesh are “not rare.”
The FDA allowed POP mesh to remain on the market even after it had been reclassified as high risk or class III, he said.
He called the 522 studies inadequate, because they were non-randomized and unblinded.
"These studies revealed the use of these products did not result in better subjective success rates than native tissue repair at one, two, or three years. In terms of risk, on the other hand, a review of the literature demonstrates the use of mesh leads to high rates of serious complications, many of which require additional surgical intervention and some of which are not amenable to surgical correction and result in harm.”
Madris Tomes, formerly with the FDA, has now formed her own company using FDA data called Device Events. While the FDA’s MAUDE database of injuries can show 500 events at a time, in a few seconds she found 139,000 reports of mesh complications with 1,107 deaths.
Specifically for POP mesh there have been 64,000 injury reports and 393 deaths associated specifically with POP mesh. She added that for every 100 adverse event reports, the OIG estimates that 66 reports are submitted and are not publicly available to view.
“Typically reports to the FDA only 17% of them are from physicians. And that's globally across all devices. With this type of mesh, that number increased to 26%. I'm not sure how many of you are physicians, but most physicians don't have a lot of time to do adversity event reporting, and they're not mandated to do so. When I see this number of adverse events, I have to think that the issues are fairly serious.”
Dr. Diana Zuckerman of the National Center for Health Research testified that mesh changes overtime and has resulted in “nightmare” outcomes for some women. “We don’t know how many women and are uncertain just how often it happens and how long it takes.”
“I don't usually like to use the term "nightmare" what I'm talking to a professional group, but I don't think you could describe the problems that some of these women have been having in any other term. These are really terrible outcomes for some women.
“So really, the only uncertainty is how often it happens and how much years it takes. I mentioned on this nightmare scenario five to 10 surges but you've heard today that it can be many, many more than 10.
“And that's the reason -- and you've also heard that sometimes these symptoms appear after five years.
“So these one-year studies are just inadequate, and even a three-year study is inadequate. You need a longer-term study to really know what's going on.”
A 522 study is not the same as a clinical trial, testified Cindy Pearson, Executive Director of the National Women’s Health Network.
While the PMA conducts randomized, large long-term blinded assessments, postmarket surveillance does not meet that same rigorous standard, she said.
"Products used chronically, in people who do not have a life-threatening condition are typically randomized, large, long-term v blinded assessment, and very scrupulous follow-up to insure a low loss to follow-up rate. Postmarket surveillance studies don't meet those standards in general, nor do they in this case.
“While it may be fair to companies, it’s not fair to women. PMA standards are what women deserve!”
In the afternoon, mesh manufacturer Boston Scientific’s Dr. Ronald Morton Jr. MD testified. Initially he turned to face the audience behind him to apologize to those injured by all transvaginal mesh. See the video here.
Miles Murphy MD, and a Boston Scientific consultant, said he had been compensated for his time but has no investment in the company. Surgical technique for transvaginal mesh has improved over time he opined and now mesh erosion is down from 11-18% to 0-8% for the Uphold with no official erosions reported.
“While it might not be for all, the availability of TVM is critical for optimizing the treatment for all patients”~ Miles Murphy, MD.
Murphy has appeared as an expert for Johnson & Johnson in product liability trials.
A statistician, Jason T. Conner Ph.D, questioned the skill set of physicians implanting mesh, which has been shown to vary. Some doctors were trained on implanting transvaginal mesh during weekend cadaver clinics.
What constitutes a “volume surgeon” was debated? Do three surgeries a year amount to a volume? Hopefully not, said chairman Dr. Keith Isaacson who opined he hoped his pilot had more than three flights under his belt when he flew home.
Ben Fisher of the FDA said that is not the agency’s definition. Dan Morgan MD suggested 12 surgeries a year or more would be considered a higher or adequate volume surgeon.
Most panelists discussed the difficulty of keeping women in a 522 study for the long-term beyond one year as essential to understanding complications. They should be extended to at least three years, the group agreed.
What is the reasonable length of time for the life of a mesh medical device? About ten years said panelists, however, that fails to square with the fact that pelvic mesh is a permanent medical device.
Industry assured the panel that the new meshes are improved with greater pore size over 1 mm of traditional meshes, which causes less shrinkage and scar formation.
I hope that’s true, said Richard Chappell, Ph.D, a statistician.
Richard Chappell, Ph.D. – " I owe it to patients who gave me such heart-rendering testimony during the 2011 version of this meeting, not to be here in another eight years saying 2019 is old-fashioned methods and devices were fine back then but now we have much better ones. "
The panelists had eight questions to answer including whether subject and objective considerations should be considered, (ie how she feels, her quality of live (QOL) versus whether her uterus is in the right place), what symptoms should be measured, what level of training surgeons should have, and what is the expected durability of a mesh repair versus a native tissue repair?
Most testified during the Q and A that there is not yet enough information yet to answer these questions.
Currently there are five PMA studies for POP mesh underway.
At least four manufacturers, J&J, Bard, Boston Scientific and Coloplast, still sell transvaginal mesh used to treat incontinence.
AUGS refers to those meshes as the “Gold Standard.”