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Patient-reported outcomes should be the priority consideration for determining whether the three synthetic mesh devices currently available for transvaginal repair of pelvic organ prolapse (POP) in the anterior vaginal compartment should remain on the market, according to the Food and Drug Administration Obstetrics and Gynecology Devices panel.
The panel was convened in February 2019 to advise the Food and Drug Administration on how it should evaluate the safety and effectiveness of the three currently marketed devices – each of which has ongoing postmarket surveillance studies – as well as any other similar devices that come up for premarket approval in the future.
The panel’s main messages: Subjective outcomes are what really matter – even more so than anatomic or objective outcomes – as does long-term follow-up.
“ “compared to native tissue repair,” said panel chair Keith Isaacson, MD, medical director of the Newton-Wellesley Hospital in Newton, Mass. “But we feel that, if we had to score [each category of outcome], about 75% should be subjective.”
The three devices currently marketed for transvaginal repair of POP (Boston Scientific’s Uphold LITE and Xenform, as well as Coloplast’s Restorelle DirectFix Anterior) are being scrutinized under a new regulatory paradigm and amid a charged backdrop of safety warnings and years of lawsuits regarding debilitating complications following surgeries that involved the implantation of synthetic vaginal mesh.
The two manufacturers of the currently available devices launched postmarket surveillance studies, called 522 studies, after the FDA issued postmarket surveillance study orders in 2012 to all manufacturers of surgical mesh for transvaginal repair of POP. (Most companies chose at the time to pull their products from the market.) This FDA action, along with a reclassification of the devices from class II to the high-risk class III, had been recommended at a 2011 meeting of the Obstetrics and Gynecology Devices panel.
In anticipation of a future reclassification, the 522 studies were designed at the time to support future premarket approval (PMA) applications, as advised by the FDA. Now, as a result of the 2016 reclassification of surgical mesh for transvaginal POP repair to class III – and the companies’ subsequent PMA applications – the FDA is reviewing the ongoing postmarket study results with a PMA lens to determine each device’s benefit/risk profile.
It’s a challenging assessment to make, FDA officials said.
The agency reported to the panel that a search of medical device reports from 2008 to 2018 identified 11,274 adverse events associated with mesh placed in the anterior vaginal compartment to treat POP. These included 10,391 reports of serious injury, 806 reports of device malfunctions, and 77 reports of death.
Findings from an FDA literature review covering the same period and also focusing on anterior and/or apical repair show that synthetic mesh may have some advantage over native tissue repair for objective effectiveness outcomes – but not necessarily subjective outcomes – over 1-3 years of follow-up. And the risks of using mesh are greater, particularly with respect to reoperation for recurrence and mesh complications, the latter of which continued beyond the first year of follow-up and through 5 years, the agency said.
Although the review may help the FDA frame its questions moving forward, it has limited utility beyond that, according to urogynecologic surgeons who testified on behalf of three professional societies. The review does not delineate differences between the newer materials used today and older mesh materials that were of heavier weight/higher mesh density and often placed using more invasive delivery systems. Nor does it offer any insight on the use of mesh for secondary repair.
“Much of the existing data on the use of transvaginal mesh in POP surgery comes from low to moderate quality, short-term studies of synthetic mesh that is no longer used in clinical practice,” said Cheryl Iglesia, MD, a Washington-based ob.gyn. who spoke to the advisory panel on behalf of the American College of Obstetricians and Gynecologists. “There’s a critical need for data from high-quality studies on the use of the newer, lightweight type 1 transvaginal meshes used in POP surgery.”
The FDA’s 522 orders requested that manufacturers conduct a randomized, controlled study or parallel cohort study comparing their device to native tissue repair. Requested effectiveness endpoints included anatomic success, subjective success, and retreatment for prolapse. For safety endpoints, the agency requested all device- and procedure-related adverse events, as well as the rate of individual adverse events, such as mesh erosion and de novo dyspareunia and urinary dysfunction. The FDA asked for all endpoints at 6-month intervals out to 24 months and at 36 months.
The panel advised that superiority should be the standard for the general population of women with POP – that mesh used in the anterior/apical vaginal compartment should be shown to be superior to native tissue repair at each time point. In specific patient populations for whom native tissue repair is not deemed feasible or appropriate, demonstrating equivalence is sufficient, they advised.
They called for “more diligent” presurgical assessments of sexual function and activity, as well as other symptoms that will be assessed later. And the panel agreed with the FDA that concomitant procedures (for example, hysterectomy and sling placement) and certain preexisting medical conditions and patient characteristics (such as obesity and diabetes) can affect outcomes and should be delineated and considered in the FDA’s evaluations and interpretation of study results.
Regarding surgeon characteristics, the panel’s biostatisticians and physicians (largely urogynecologists, but also one community ob.gyn.) advised the FDA to pay attention to surgeon training, experience, and volume, but they declined to offer any specific recommendations. Discussions often came back to the value of a registry that would capture both surgeon data and patient experience. And throughout the panel’s discussion, surgeons stepped away from the main questions at hand and emphasized the individualized nature of risk-benefit ratios and decision making.
Registries have been successfully used for cardiology and orthopedic implants and, within obstetrics and gynecology, for assisted reproductive technologies, Dr. Iglesia said in an interview after the meeting. “We have models … we just need to make it easy for physicians, using our EMRs. But I’m hopeful.”
The American Urogynecologic Society (AUGS) operates a quality improvement registry (AQUIRE) that is collecting information on surgical and nonsurgical treatment of POP and stress urinary incontinence – including surgical complications – from a diverse group of physicians, not just those at academic medical centers. AUGS is growing its registry this year to include device identifiers and patient-reported outcomes that are sent directly to the registry by the patient.
The panel generally agreed that postmarket follow-up of synthetic mesh for transvaginal anterior repair of POP should extend up to 5 years, Dr. Isaacson said, though “from the patients’ perspective, 10 years of experience [is meaningful].”
Geoffrey Cundiff, MD, who is AUGS president, told the committee that there are lessons to be gleaned from the CARE trial, which looked at outcomes up to 7 years after abdominal sacrocolpopexy (JAMA. 2013 May 15;309[19]:2016-24). “At 7 years, the complications [including rates of mesh erosion] had increased,” he said. “It’s a different procedure, but it’s a good example.”
Prior to its deliberations, the panel heard preliminary results of the ongoing SUPeR trial (Female Pelvic Med Reconstr Surg. 2016 Jul-Aug;22[4]:182-9), a randomized, controlled superiority trial of vaginal hysterectomy with suture apical suspension versus uterine conservation with vaginal mesh (Boston Scientific’s Uphold LITE) hysteropexy for uterovaginal prolapse. Researchers have found comparable rates of primary outcome success – no objective prolapse beyond the hymen, no retreatment, and no bulge symptoms – through 36 months and no differences in patient-reported outcomes thus far.
Hysteroplexy mesh exposure rates were approximately 8% at 36 months, and suture exposure and excessive granulation were 11%-20% in the hysterectomy group. None of these exposure cases has required reoperation. Both groups have shown improvements in sexual function and decreases in dyspareunia, said Charles W. Nager, MD, a San Diego ob.gyn. who is primary investigator of the trial.
The trial is sponsored by the Pelvic Floor Disorders Network of the National Institute of Child Health and Human Development, as was the CARE trial of abdominal sacrocolpopexy. It is following patients for 60 months and collecting data every 6 months, including data from validated functional and quality of life assessments. Patients were masked to their treatment assignment to eliminate patient reporting bias. At 36 months, approximately three-quarters of the patients in each group remained masked.
In addition to the ongoing 522 studies for anterior/apical prolapse, there is another 522 study underway of a mesh device designed for transvaginal repair of total prolapse (the Acell Matristem Pelvic Floor Repair Matrix). In addition, Coloplast is studying a mesh device designed for posterior/apical prolapse (Restorelle DirectFix) as part of its 522 study. Neither device is being marketed currently, however.
Patient-reported outcomes should be the priority consideration for determining whether the three synthetic mesh devices currently available for transvaginal repair of pelvic organ prolapse (POP) in the anterior vaginal compartment should remain on the market, according to the Food and Drug Administration Obstetrics and Gynecology Devices panel.
The panel was convened in February 2019 to advise the Food and Drug Administration on how it should evaluate the safety and effectiveness of the three currently marketed devices – each of which has ongoing postmarket surveillance studies – as well as any other similar devices that come up for premarket approval in the future.
The panel’s main messages: Subjective outcomes are what really matter – even more so than anatomic or objective outcomes – as does long-term follow-up.
“ “compared to native tissue repair,” said panel chair Keith Isaacson, MD, medical director of the Newton-Wellesley Hospital in Newton, Mass. “But we feel that, if we had to score [each category of outcome], about 75% should be subjective.”
The three devices currently marketed for transvaginal repair of POP (Boston Scientific’s Uphold LITE and Xenform, as well as Coloplast’s Restorelle DirectFix Anterior) are being scrutinized under a new regulatory paradigm and amid a charged backdrop of safety warnings and years of lawsuits regarding debilitating complications following surgeries that involved the implantation of synthetic vaginal mesh.
The two manufacturers of the currently available devices launched postmarket surveillance studies, called 522 studies, after the FDA issued postmarket surveillance study orders in 2012 to all manufacturers of surgical mesh for transvaginal repair of POP. (Most companies chose at the time to pull their products from the market.) This FDA action, along with a reclassification of the devices from class II to the high-risk class III, had been recommended at a 2011 meeting of the Obstetrics and Gynecology Devices panel.
In anticipation of a future reclassification, the 522 studies were designed at the time to support future premarket approval (PMA) applications, as advised by the FDA. Now, as a result of the 2016 reclassification of surgical mesh for transvaginal POP repair to class III – and the companies’ subsequent PMA applications – the FDA is reviewing the ongoing postmarket study results with a PMA lens to determine each device’s benefit/risk profile.
It’s a challenging assessment to make, FDA officials said.
The agency reported to the panel that a search of medical device reports from 2008 to 2018 identified 11,274 adverse events associated with mesh placed in the anterior vaginal compartment to treat POP. These included 10,391 reports of serious injury, 806 reports of device malfunctions, and 77 reports of death.
Findings from an FDA literature review covering the same period and also focusing on anterior and/or apical repair show that synthetic mesh may have some advantage over native tissue repair for objective effectiveness outcomes – but not necessarily subjective outcomes – over 1-3 years of follow-up. And the risks of using mesh are greater, particularly with respect to reoperation for recurrence and mesh complications, the latter of which continued beyond the first year of follow-up and through 5 years, the agency said.
Although the review may help the FDA frame its questions moving forward, it has limited utility beyond that, according to urogynecologic surgeons who testified on behalf of three professional societies. The review does not delineate differences between the newer materials used today and older mesh materials that were of heavier weight/higher mesh density and often placed using more invasive delivery systems. Nor does it offer any insight on the use of mesh for secondary repair.
“Much of the existing data on the use of transvaginal mesh in POP surgery comes from low to moderate quality, short-term studies of synthetic mesh that is no longer used in clinical practice,” said Cheryl Iglesia, MD, a Washington-based ob.gyn. who spoke to the advisory panel on behalf of the American College of Obstetricians and Gynecologists. “There’s a critical need for data from high-quality studies on the use of the newer, lightweight type 1 transvaginal meshes used in POP surgery.”
The FDA’s 522 orders requested that manufacturers conduct a randomized, controlled study or parallel cohort study comparing their device to native tissue repair. Requested effectiveness endpoints included anatomic success, subjective success, and retreatment for prolapse. For safety endpoints, the agency requested all device- and procedure-related adverse events, as well as the rate of individual adverse events, such as mesh erosion and de novo dyspareunia and urinary dysfunction. The FDA asked for all endpoints at 6-month intervals out to 24 months and at 36 months.
The panel advised that superiority should be the standard for the general population of women with POP – that mesh used in the anterior/apical vaginal compartment should be shown to be superior to native tissue repair at each time point. In specific patient populations for whom native tissue repair is not deemed feasible or appropriate, demonstrating equivalence is sufficient, they advised.
They called for “more diligent” presurgical assessments of sexual function and activity, as well as other symptoms that will be assessed later. And the panel agreed with the FDA that concomitant procedures (for example, hysterectomy and sling placement) and certain preexisting medical conditions and patient characteristics (such as obesity and diabetes) can affect outcomes and should be delineated and considered in the FDA’s evaluations and interpretation of study results.
Regarding surgeon characteristics, the panel’s biostatisticians and physicians (largely urogynecologists, but also one community ob.gyn.) advised the FDA to pay attention to surgeon training, experience, and volume, but they declined to offer any specific recommendations. Discussions often came back to the value of a registry that would capture both surgeon data and patient experience. And throughout the panel’s discussion, surgeons stepped away from the main questions at hand and emphasized the individualized nature of risk-benefit ratios and decision making.
Registries have been successfully used for cardiology and orthopedic implants and, within obstetrics and gynecology, for assisted reproductive technologies, Dr. Iglesia said in an interview after the meeting. “We have models … we just need to make it easy for physicians, using our EMRs. But I’m hopeful.”
The American Urogynecologic Society (AUGS) operates a quality improvement registry (AQUIRE) that is collecting information on surgical and nonsurgical treatment of POP and stress urinary incontinence – including surgical complications – from a diverse group of physicians, not just those at academic medical centers. AUGS is growing its registry this year to include device identifiers and patient-reported outcomes that are sent directly to the registry by the patient.
The panel generally agreed that postmarket follow-up of synthetic mesh for transvaginal anterior repair of POP should extend up to 5 years, Dr. Isaacson said, though “from the patients’ perspective, 10 years of experience [is meaningful].”
Geoffrey Cundiff, MD, who is AUGS president, told the committee that there are lessons to be gleaned from the CARE trial, which looked at outcomes up to 7 years after abdominal sacrocolpopexy (JAMA. 2013 May 15;309[19]:2016-24). “At 7 years, the complications [including rates of mesh erosion] had increased,” he said. “It’s a different procedure, but it’s a good example.”
Prior to its deliberations, the panel heard preliminary results of the ongoing SUPeR trial (Female Pelvic Med Reconstr Surg. 2016 Jul-Aug;22[4]:182-9), a randomized, controlled superiority trial of vaginal hysterectomy with suture apical suspension versus uterine conservation with vaginal mesh (Boston Scientific’s Uphold LITE) hysteropexy for uterovaginal prolapse. Researchers have found comparable rates of primary outcome success – no objective prolapse beyond the hymen, no retreatment, and no bulge symptoms – through 36 months and no differences in patient-reported outcomes thus far.
Hysteroplexy mesh exposure rates were approximately 8% at 36 months, and suture exposure and excessive granulation were 11%-20% in the hysterectomy group. None of these exposure cases has required reoperation. Both groups have shown improvements in sexual function and decreases in dyspareunia, said Charles W. Nager, MD, a San Diego ob.gyn. who is primary investigator of the trial.
The trial is sponsored by the Pelvic Floor Disorders Network of the National Institute of Child Health and Human Development, as was the CARE trial of abdominal sacrocolpopexy. It is following patients for 60 months and collecting data every 6 months, including data from validated functional and quality of life assessments. Patients were masked to their treatment assignment to eliminate patient reporting bias. At 36 months, approximately three-quarters of the patients in each group remained masked.
In addition to the ongoing 522 studies for anterior/apical prolapse, there is another 522 study underway of a mesh device designed for transvaginal repair of total prolapse (the Acell Matristem Pelvic Floor Repair Matrix). In addition, Coloplast is studying a mesh device designed for posterior/apical prolapse (Restorelle DirectFix) as part of its 522 study. Neither device is being marketed currently, however.
Patient-reported outcomes should be the priority consideration for determining whether the three synthetic mesh devices currently available for transvaginal repair of pelvic organ prolapse (POP) in the anterior vaginal compartment should remain on the market, according to the Food and Drug Administration Obstetrics and Gynecology Devices panel.
The panel was convened in February 2019 to advise the Food and Drug Administration on how it should evaluate the safety and effectiveness of the three currently marketed devices – each of which has ongoing postmarket surveillance studies – as well as any other similar devices that come up for premarket approval in the future.
The panel’s main messages: Subjective outcomes are what really matter – even more so than anatomic or objective outcomes – as does long-term follow-up.
“ “compared to native tissue repair,” said panel chair Keith Isaacson, MD, medical director of the Newton-Wellesley Hospital in Newton, Mass. “But we feel that, if we had to score [each category of outcome], about 75% should be subjective.”
The three devices currently marketed for transvaginal repair of POP (Boston Scientific’s Uphold LITE and Xenform, as well as Coloplast’s Restorelle DirectFix Anterior) are being scrutinized under a new regulatory paradigm and amid a charged backdrop of safety warnings and years of lawsuits regarding debilitating complications following surgeries that involved the implantation of synthetic vaginal mesh.
The two manufacturers of the currently available devices launched postmarket surveillance studies, called 522 studies, after the FDA issued postmarket surveillance study orders in 2012 to all manufacturers of surgical mesh for transvaginal repair of POP. (Most companies chose at the time to pull their products from the market.) This FDA action, along with a reclassification of the devices from class II to the high-risk class III, had been recommended at a 2011 meeting of the Obstetrics and Gynecology Devices panel.
In anticipation of a future reclassification, the 522 studies were designed at the time to support future premarket approval (PMA) applications, as advised by the FDA. Now, as a result of the 2016 reclassification of surgical mesh for transvaginal POP repair to class III – and the companies’ subsequent PMA applications – the FDA is reviewing the ongoing postmarket study results with a PMA lens to determine each device’s benefit/risk profile.
It’s a challenging assessment to make, FDA officials said.
The agency reported to the panel that a search of medical device reports from 2008 to 2018 identified 11,274 adverse events associated with mesh placed in the anterior vaginal compartment to treat POP. These included 10,391 reports of serious injury, 806 reports of device malfunctions, and 77 reports of death.
Findings from an FDA literature review covering the same period and also focusing on anterior and/or apical repair show that synthetic mesh may have some advantage over native tissue repair for objective effectiveness outcomes – but not necessarily subjective outcomes – over 1-3 years of follow-up. And the risks of using mesh are greater, particularly with respect to reoperation for recurrence and mesh complications, the latter of which continued beyond the first year of follow-up and through 5 years, the agency said.
Although the review may help the FDA frame its questions moving forward, it has limited utility beyond that, according to urogynecologic surgeons who testified on behalf of three professional societies. The review does not delineate differences between the newer materials used today and older mesh materials that were of heavier weight/higher mesh density and often placed using more invasive delivery systems. Nor does it offer any insight on the use of mesh for secondary repair.
“Much of the existing data on the use of transvaginal mesh in POP surgery comes from low to moderate quality, short-term studies of synthetic mesh that is no longer used in clinical practice,” said Cheryl Iglesia, MD, a Washington-based ob.gyn. who spoke to the advisory panel on behalf of the American College of Obstetricians and Gynecologists. “There’s a critical need for data from high-quality studies on the use of the newer, lightweight type 1 transvaginal meshes used in POP surgery.”
The FDA’s 522 orders requested that manufacturers conduct a randomized, controlled study or parallel cohort study comparing their device to native tissue repair. Requested effectiveness endpoints included anatomic success, subjective success, and retreatment for prolapse. For safety endpoints, the agency requested all device- and procedure-related adverse events, as well as the rate of individual adverse events, such as mesh erosion and de novo dyspareunia and urinary dysfunction. The FDA asked for all endpoints at 6-month intervals out to 24 months and at 36 months.
The panel advised that superiority should be the standard for the general population of women with POP – that mesh used in the anterior/apical vaginal compartment should be shown to be superior to native tissue repair at each time point. In specific patient populations for whom native tissue repair is not deemed feasible or appropriate, demonstrating equivalence is sufficient, they advised.
They called for “more diligent” presurgical assessments of sexual function and activity, as well as other symptoms that will be assessed later. And the panel agreed with the FDA that concomitant procedures (for example, hysterectomy and sling placement) and certain preexisting medical conditions and patient characteristics (such as obesity and diabetes) can affect outcomes and should be delineated and considered in the FDA’s evaluations and interpretation of study results.
Regarding surgeon characteristics, the panel’s biostatisticians and physicians (largely urogynecologists, but also one community ob.gyn.) advised the FDA to pay attention to surgeon training, experience, and volume, but they declined to offer any specific recommendations. Discussions often came back to the value of a registry that would capture both surgeon data and patient experience. And throughout the panel’s discussion, surgeons stepped away from the main questions at hand and emphasized the individualized nature of risk-benefit ratios and decision making.
Registries have been successfully used for cardiology and orthopedic implants and, within obstetrics and gynecology, for assisted reproductive technologies, Dr. Iglesia said in an interview after the meeting. “We have models … we just need to make it easy for physicians, using our EMRs. But I’m hopeful.”
The American Urogynecologic Society (AUGS) operates a quality improvement registry (AQUIRE) that is collecting information on surgical and nonsurgical treatment of POP and stress urinary incontinence – including surgical complications – from a diverse group of physicians, not just those at academic medical centers. AUGS is growing its registry this year to include device identifiers and patient-reported outcomes that are sent directly to the registry by the patient.
The panel generally agreed that postmarket follow-up of synthetic mesh for transvaginal anterior repair of POP should extend up to 5 years, Dr. Isaacson said, though “from the patients’ perspective, 10 years of experience [is meaningful].”
Geoffrey Cundiff, MD, who is AUGS president, told the committee that there are lessons to be gleaned from the CARE trial, which looked at outcomes up to 7 years after abdominal sacrocolpopexy (JAMA. 2013 May 15;309[19]:2016-24). “At 7 years, the complications [including rates of mesh erosion] had increased,” he said. “It’s a different procedure, but it’s a good example.”
Prior to its deliberations, the panel heard preliminary results of the ongoing SUPeR trial (Female Pelvic Med Reconstr Surg. 2016 Jul-Aug;22[4]:182-9), a randomized, controlled superiority trial of vaginal hysterectomy with suture apical suspension versus uterine conservation with vaginal mesh (Boston Scientific’s Uphold LITE) hysteropexy for uterovaginal prolapse. Researchers have found comparable rates of primary outcome success – no objective prolapse beyond the hymen, no retreatment, and no bulge symptoms – through 36 months and no differences in patient-reported outcomes thus far.
Hysteroplexy mesh exposure rates were approximately 8% at 36 months, and suture exposure and excessive granulation were 11%-20% in the hysterectomy group. None of these exposure cases has required reoperation. Both groups have shown improvements in sexual function and decreases in dyspareunia, said Charles W. Nager, MD, a San Diego ob.gyn. who is primary investigator of the trial.
The trial is sponsored by the Pelvic Floor Disorders Network of the National Institute of Child Health and Human Development, as was the CARE trial of abdominal sacrocolpopexy. It is following patients for 60 months and collecting data every 6 months, including data from validated functional and quality of life assessments. Patients were masked to their treatment assignment to eliminate patient reporting bias. At 36 months, approximately three-quarters of the patients in each group remained masked.
In addition to the ongoing 522 studies for anterior/apical prolapse, there is another 522 study underway of a mesh device designed for transvaginal repair of total prolapse (the Acell Matristem Pelvic Floor Repair Matrix). In addition, Coloplast is studying a mesh device designed for posterior/apical prolapse (Restorelle DirectFix) as part of its 522 study. Neither device is being marketed currently, however.