The Pelvic Floor Disorders Network: Evolution Over Two Decades of Female Pelvic Floor Research

Abstract

Importance:

To describe research initiatives, evolution and processes of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) supported Pelvic Floor Disorders Network (PFDN). This may be of interest and inform researchers wishing to conduct multisite coordinated research initiatives as well as to provide perspective to all urogynecologists regarding how the PFDN has evolved and functions.

Study Design:

Principal Investigators (PIs) of several PFDN clinical sites and Data Coordinating Center (DCC) describe more than 20 years of development and maturation of the PFDN.

Results:

Over two decades, the PFDN used an intentionally driven approach to answering clinically important questions to inform the surgical and non-surgical care of women with pelvic floor disorders (PFDs) including pelvic organ prolapse (POP), urinary incontinence (UI) and fecal incontinence (FI). From its inception, the PFDN refined network procedures and processes affecting trial design, protocol development and standardization of outcomes and publications. This strategy resulted in a credible, robust and productive portfolio of randomized clinical trials, secondary analyses, prospective cohort and supplementary studies emphasizing the use of validated patient reported outcomes, longer-term outcomes, an increase in translational science aims and standardized, long-term collection of adverse events.

Conclusions:

The processes PFDN has developed and implemented have led to impactful research initiatives in women’s pelvic floor disorders. Patient participants and research coordinators have been an integral part of this contribution. Through consistent funding and committed investigators, the state of science in the surgical and non-surgical care and understanding of PFD pathophysiology has been advanced.

Introduction

Pelvic floor disorders (PFDs) are conditions that affect the support and function of the pelvic organs and lower urinary and gastrointestinal tracts, such as pelvic organ prolapse (POP), urinary and fecal incontinence (UI and FI). Historically under-recognized, PFDs are common among women, and significantly affect quality of life, daily activities, and sexual function.¹ Despite the societal impact and cost of these conditions, the medical and lay communities traditionally underappreciate their incidence and significance. Recognizing the need for a portfolio of comprehensive, rigorous studies on PFDs, the National Institutes of Health’s (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) established the Pelvic Floor Disorders Network (PFDN) in 2001 to encourage multi-disciplinary collaborative research on PFDs to improve care. The overarching goal of the PFDN is to fill critical knowledge gaps in the treatment of PFDs. PFDN research includes not only the collection and dissemination of objective and patient reported outcomes of evidence-based treatment of PFDs, but also translational work exploring the underlying pathogenesis of PFDs.

The PFDN was established and currently exists as a multicenter clinical program that has been continuously funded since its launch in 2001 by the Eunice Kennedy Shriver NICHD through a cooperative mechanism, in which NIH staff are actively involved. Funding cycles are 5 years in length, and the process is announced through companion competitive Request for Applications (RFA), for 6–8 clinical sites and a data coordinating center (DCC). The DCC is responsible for statistical aspects of trial design, data management and quality assurance, study training coordination, statistical analysis, and management of protocol funds.

Clinical center applicants provide information regarding their research experience and pool of potential participants with PFDs, and are also required to submit a concept proposal for a randomized trial, prospective cohort or translational study. Applications are scored by an independent scientific review committee through the Center for Scientific Review (CSR). Participating centers are chosen based on their proven dedication to research, performance in research endeavors, clinical expertise, and track record for enrollment and long-term retention of clinical trial participants. With each new cycle, the composition of the PFDN changes with expected turnover of clinical sites as well as the DCC (Table 1).

Table 1.

Pelvic Floor Disorders Network Site Locations – 2001 - Present

Site	PI	Cycle 1 2001–2006	Cycle 2 2006–2011	Cycle 3 2011–2016	Cycle 4 2016–2022	Cycle 5 2022–2027
University of Alabama at Birmingham	Holly E Richter	X	X	X	X
Baylor University Medical Center	Paul Fine	X
Brown University/Womens and Infants Hospital	Deborah L Myers; Vivian Sung (2014*)			X	X	X
University of California at San Diego	Charles W Nager; Emily Lukacz (2015*); Emily Lukacz and Shawn Menefee (co-PIs 2016*)		X	X	X	X
Cleveland Clinic	Matthew D Barber; Marie Fidela Paraiso (2017*)		X	X	X
Duke University	Anthony Visco; Nazema Siddiqui (2022*)	X (under UNC)	X (under UNC)	X	X	X
University of Texas Southwestern	Joseph I Schaffer; David Rahn (2016*)		X	X	X	X
Loyola University	Linda Brubaker	X	X	X
University of Michigan (Data Coordinating Center)	Cathy Spino; M Brown	X	X	X
University of Chicago	Kim Kenton					X
University of New Mexico	Rebecca G Rogers; Yuko Komesu (2017*)			X	X
University of Pennsylvania	Lily Arya; Heidi Harvie (2020*)			X	X	X
University of Pittsburgh/Magee-Womens Research Institute (Also Ancillary site (UMich) for ABC Trial, 2009–11)	Halina M Zyczynski	X		X	X
RTI International (Data Coordinating Center)	Dennis Wallace; Marie Gantz (2015*)			X	X	X
University of Utah	Ingrid Nygaard		X
University of Iowa	Karl Kreder; Ingrid Nygaard	X
Johns Hopkins	Geoffrey Cundiff	X

^*Years noted in parenthesis indicate a change in PI

Over time, the PFDN funding structure has evolved. Each grant cycle has included a standardized base budget for the Principal Investigator (PI), alternate-PI, research coordinator (RC), and travel to quarterly steering committee meetings. Initially, all funding for research participants was awarded to the sites in a restricted fund that was “earned” as participants were enrolled. In subsequent cycles, investigator and coordinator effort and travel funds continued to be awarded prospectively, but protocol-specific funds were “earned” upon completion of trial milestones (study visits) and distributed from the DCC to individual sites through “capitation dollars.” The capitation budget is developed concomitantly with the trial design by the protocol committee. Implementation of capitated budgets equitably addressed site-specific differences in enrollment and enabled funding of ancillary sites (approved after discussion at the Steering Committee (SC) when study enrollment lagged behind projections, as well as non-continuing sites for their efforts in long-term follow-up of study participants. Study recruitment by site is a priority agenda at each SC meeting, with discussion of successful recruitment strategies presented by high-performing sites.

An important addition to the most recent request for applications for the PFDN (Funding Opportunity Announcement RFA-HD-22–021) included an agreement by network sites to consider trial concepts from outside the PFDN. Participation of non-PFDN sites aims to increase the external generalizability and the overall scientific growth of ideas and studies addressing important pelvic floor research initiatives. A separate funding opportunity (PAR-23–037) that opened in May 2023 provides an avenue for investigators to propose studies to be conducted within an existing NICHD network. This mechanism aims to ensure open access to the mechanisms and infrastructure of the networks to conduct meaningful clinical trials proposed by external sites.

There is increasing recognition that partnerships between investigators and industry are necessary for the growth of evidence-based approaches to the treatment of pelvic floor disorders. The PFDN has partnered with industry to critically assess innovative surgical devices and procedures, while maintaining well-defined roles between industry and the PFDN. Specifically, the PFDN has retained control of the science, through study design, analyses and manuscript creation that is independent of its industry partner. Any support from industry is carefully acknowledged in manuscripts from the study, as in the case of the SUPeR trial, in which Boston Scientific provided partial funding through an unrestricted research grant.² These defined relationships are essential to ensure the integrity of the PFDN’s work, while acknowledging that there are real benefits for scientific advancement from these relationships.

Since 2001, the PFDN has conducted 15 index randomized controlled trials (RCTs), prospective cohort studies and basic science studies enrolling over 5,000 women, resulting in an invaluable data pool, more than 150 publications, and many landmark papers. Major comparative effectiveness trials address outcomes of native tissue and mesh augmented prolapse repair including hysteropexy, non-surgical management of SUI, lifestyle interventions, pharmacological agents and neuromodulation for the treatment of urgency urinary incontinence (UUI) and FI as well as functional and anatomic outcomes of obliterative surgery, obstetric anal sphincter injuries sustained by primiparas, and adjuvant perioperative pelvic floor strengthening in prolapse and stress urinary incontinence (SUI) surgery (Table 2).^3–17 The PFDN conducted one of the first trials utilizing a patient-reported outcome solely as the primary outcome for mixed urinary incontinence (ESTEEM).¹³

Table 2:

Network Index Studies

Journal	Study Name	Primary Outcome Timepoint/Follow-up	Study Type	Total Participants, N	Mean Age, yrs				Race/Ethnicity (%)
					Burch Group N=157		Control Group N=165		Burch Group N=157, %		Control Group N=165, %
3N Engl J Med 2006;354:1557–66	The Colpopexy and Urinary Reduction Efforts (CARE)	3 months/2 yrs	RCT	322	62.4 ± 9.7		60.3 ± 10.6		White: 96.2 Black: 3.2 Hispanic: 1.3 Other: 0.6		White: 89.7 Black: 7.3 Hispanic: 4.2 Other: 3.0
					Sphincter Tear N=407		Vaginal Control N=390	Cesarean Control N=124	Sphincter Tear N=407, %		Vaginal Control N=390, %	Cesarean Control N=124, %
4Obstet Gynecol 2006;108:863–72	The Childbirth and Pelvic Symptoms (CAPS)	6 weeks/6months	Prospective cohort	921	27.6 ± 6.0		25.8 ± 5.7	30.2 ± 6.6	White:73.8 Black:15.4 Hispanic:7.4 Other:6.2		White: 66.3 Black: 24.4 Hispanic:7.2 Other: 5.9	White: 78.2 Black: 13.7 Hispanic:5.7 Other: 5.7
					BoNT-A N=28		Placebo N=15		BoNT-A N=28, %		Placebo N=15, %
5J Urol 2008;180:217–222	Refractory Idiopathic Urge Urinary Incontinence and Botulinum A Injection (RUBI)	>/=2 months/12 months	RCT	43	64.7 ± 14.5		69.2 ± 13.5		White: 93 Black: 7		White: 100 Black: 0
					N=152				N=152, %
6Int Urogynecol J Pelvic Floor Dysfunct 2008;19:1603–09	Colpocleisis	3 months/12 months	Cohort	152	79.3 ± 5.6				White: 92 Black: 8 Hispanic: 2
					Combined N=150		Behavioral N=146	Pessary N=149	Combined N=150, %		Behavioral N=146 ,%	Pessary N=149, %
7Obstet Gynecol 2010;115:609–17	Ambulatory Treatments for Leakage Associated with Stress. Pessary vs Pelvic Floor Muscle Therapy vs Combined Therapy: (ATLAS)	3 months/6 and 12 months	RCT	445	49.5 ± 11.8		49.6 ± 13.0	50.2 ± 11.0	White: 81.3 Black: 13.3 Other: 5.3		White: 90.4 Black: 6.8 Other: 2.7	White: 84.5 Black: 10.1 Other: 5.4
					Sling N=165		Sham N=172		Sling N=165, %		Sham N=172, %
8N Engl J Med 2012;366:2358–67	Outcomes Following Vaginal Prolapse Repair and Midurethral Sling (OPUS)	3 months/12 months	RCT	337	63.4 ± 10.8		62.2 ± 10.2		White: 87 Black: 6 Hispanic: 13 Other: 5		White: 83 Black: 8 Hispanic: 16 Other: 8
					Anticholinergic Drug N=126		OnabotulinumtoxinA N=121		Anticholinergic Drug N=126, %		OnabotulinumtoxianA N=121, %
9N Engl J Med 2012;367:1803–13	Anticholinergics vs Botox Comparison in Women with Urge Incontinence (ABC)	6 months/12 months	RCT	247	56.7 ± 11.6		59.3 ± 10.8		White: 78 Black: 18 Hispanic: 17 Other: 4		White: 79 Black: 15 Hispanic: 18 Other: 6
					BPMT Group Surgical Group				BMPT Group Surgical Group
					BMPT N=186	Usual Care N=188	Uterosacral Ligament Suspension N=188	Sacrospinous Ligament Fixation N=186	BMPT N=186, %	Usual Care N=188,%	Uterosacral Ligament Suspension N=188, %	Sacrospinous Ligament Fixation N=186, %
10JAMA 2014;311:1023–34	Operations and Pelvic Muscle Training in the Management of Apical Support Loss (OPTIMAL)	2 years	RCT	374	57.5 ± 10.9	56.9 ± 10.9	57.3 ±10.8	57.2 ± 11.0	White:82.8 Black: 8.1 Hispanic: 20.4 Other: 8.1	White: 85.6 Black: 3.7 Hispanic: 19.7 Other: 8.5	White: 84 Black: 6.4 Hispanic: 21.8 Other: 9.6	White: 84.4 Black: 5.4 Hispanic: 18.3 Other: 7
					OnabotulinumtoxinA N=190		Sacral Neuromodulation N=174		OnabotulinumtoxinA N=190, %		Sacral Neuromodulation N=174, %
11JAMA 2016;316:1366–1374	Refractory Overactive Bladder: Sacral Neuromodulation vs Botulinum Toxin Assessment (ROSETTA)	6 months	RCT	364	62.9 ± 11.5		63.1 ± 11.8		White: 81 Black: 12 Hispanic: 9 Other: 7		White: 86 Black: 9 Hispanic: 6 Other: 5
					Loperamide N=160	Placebo N=114	Exercise + Biofeedback N=154	Education Only N=120	Loperamide N=160, %	Placebo N=114, %	Exercise + Biofeedback N=154, %	Education Only N=120, %
12Lancet Gastroenterol Hepatol 2019;4:698–710	Controlling Anal Incontinence by Performing Anal Exercises with Biofeedback or Loperamide (CAPABLe)	24 weeks	RCT	300	*64.4 [58.1, 71.4]	*63.3 [56.1, 71.4]	*64.5 [58.3, 72.2]	*64.0 [56.4, 70.0]	White: 79.5 Black: 15.2 Hispanic: 8.8 Other: 2.3	White: 78.4 Black: 16 Hispanic: 8.8 Other: 3.2	White: 78.6 Black: 15.5 Hispanic: 9.5 Other: 2.4	White: 79.7 Black: 15.6 Hispanic: 7.8 Other: 3.1
					Combined Sling and Training N=235		Sling Only N=229		Combined Sling and Training N=235, %		Sling Only N=229, %
13JAMA 2019;322:1066–1076	Effects of Surgical Treatment Enhanced with Exercise for Mixed Urinary Incontinence (ESTEEM)	12 months	RCT	464	54.3 ± 11.0		53.6 ± 10.4		White: 77.7 Black: 9.4 Hispanic: 21.0 Other: 8.2		White: 79.4 Black: 8.3 Hispanic: 24.9 Other: 10.1
					Hysteropexy N=88		Vaginal Hysterectomy N=87		Hysteropexy N=88, %		Vaginal Hysterectomy N=87, %
14JAMA 2019; 322: 1054–1065	A Randomized Trial of Vaginal Surgery for Uterovaginal prolapse: Vaginal Hysterectomy with Native Tissue Vault Suspension vs Mesh Hysteropexy Suspension (Study of Uterine Prolapse Procedures-Randomized Trial (SUPeR)	36 Months/5 years, 10 years	RCT	183	65.5 ± 7.3		66.2 ± 7.4		White: 83.0 Black: 9.0 Hispanic: 11.0 Other: 6.0		White: 89.0 Black: 3.0 Hispanic: 8.0 Other: 1.0
					PTNS N=111			Sham N=55	PTNS N=111, %			Sham N=55, %
15Am J Gastroenterol 2022; 117; 654–667	NeurOmodulaTion for Accidental Bowel Leakage (NOTABLE)	12 weeks	RCT	166	63.5 ± 11.9			63.8 ± 11.2	White: 85.6 Black: 9.0 Hispanic: 9.0			White: 70.9 Black: 16.4 Hispanic: 10.9
					Native Tissue N=123		TV Mesh N=121	Sacrocolpopexy N=116	Native Tissue N=123, %		TV Mesh N=121, %	Sacrocolpo-pexy N=116, %
16JAMA Surgery, 2024. In Press, Published online May 22, 2024	Apical Suspension Repair for Vault Prolapse in a Three-Arm Randomized Trial (ASPIRE)	36 months/ 5 years, 10 years	RCT	360	66.4 ± 8.5		65.4 ± 8.6	66.4 ± 9.0	White: 82.1 Black: 8.1 Hispanic: 17.6 Other: 3.3		White: 84.3 Black: 10.7 Hispanic: 12.7 Other: 1	White: 85.3 Black: 10.3 Hispanic: 10.3 Other: 2.6
					MUS N=66			Botox N=71	MUS N=66, %			Botox N=71, %
17Urogynecology (Phila);2024:Jan 11;doi 10.1097/SPV.0000000000001422 Analyses in process	Treatment for Mixed Urinary Incontinence: Midurethral Sling vs Botox A (MUSA)	6 months/12 months	RCT	150	59.0 ± 11.7			59.1 ± 11.4	White: 82 Black: 15 Hispanic: 9			White: 77 Black: 14 Hispanic: 21

The PFDN collaborates with the broader scientific community through publications, conference presentations, and sharing data in a central publicly available repository, the NICHD Data and Specimen Hub (DASH). The PFDN continues to provide a robust framework for studying all areas of pelvic floor disorders. Its structure has been steadily developed, modified, and adapted over more than two decades to create a clinical trials and translational studies network that is larger, stronger, and more diverse than at inception. The following description outlines key points of the network evolution, highlights key achievements, milestones, and lessons learned along the way.

PFDN Organization and Supporting Entities

Figure 1 depicts the PFDN’s organizational structure which includes an SC composed of the PIs, Alternate PIs (who can serve as PI if the PI departs an institution or is unavailable), Co-Investigators and committed research staff from the clinical centers and DCC, who partner with the NICHD-employed Project Scientist and an independent external SC Chair. The SC Chair is recruited by the NICHD Project Officer for facilitating SC discussions including critical development of the design, implementation, and analysis of clinical trials. Various other committees, as outlined in a Policy and Procedures manual, oversee areas such as publications, the biorepository, adverse event adjudication as well as other policies that help maintain study standardization and oversight. Trial conduct, including ongoing review of progress and possible redirection of activities to improve performance and cooperation requires frequent communication of the protocol committee with the SC, PFDN Advisory Board (AB) and the Data and Safety Monitoring Board (DSMB) (Figure 1).

Figure 1. Organizational Structure of the Pelvic Floor Disorders Network.

The Advisory Board is an external peer review group, recruited by NICHD that advises the Steering Committee on the scientific scope of research in the PFDN, provides review of mini-protocols and research consents in the context of the direction of the research, and provides advice on the potential impact of proposed studies. Members of the Advisory Board are separate and distinct from the DSMB and are not affiliated with research being conducted by the Network. The PFDN Advisory Board follows NIH guidelines for advisory boards. The Advisory Board is convened at least once per year, usually when one or more mini-protocol(s) and consent(s) are available for review.

The Data & Safety Monitoring Board, selected by NICHD, is charged with ensuring the safety of study participants and to provide NICHD with advice on the safe conduct of Network studies. The DSMB also advises NICHD on research design issues, data quality and analysis, and ethical and human subject aspects of studies. The DSMB reviews interim reports provided by the DCC of participant accrual, adverse events, data quality metrics, and any pre-specific interim analyses of outcome measures and provides recommendations to the NICHD Project Scientist and Program Officer. The DSMB may recommend termination or suspension of a trial to NICHD based on, but not limited to, the following:

• A clear advantage to an experimental group has been shown, in accordance with the planned statistical boundary for interim hypothesis testing

• Patient safety would be compromised by continuation of the study

• Severe unanticipated problems occur regarding study conduct (i.e., inadequate recruitment or problems with supplies, etc.)

The NICHD reserves the right to terminate or curtail a study under a range of scenarios including but not limited to: (a) failure to implement the study protocol (b) a substantial shortfall in subject recruitment, follow-up, data reporting and dissemination, quality control, or other major breach of the protocol (c) substantive changes in the agreed-upon protocol with which NIH does not concur (d) reaching a major study objective substantially ahead of schedule with persuasive statistical evidence (e) human subject safety or ethical issues that may dictate a premature termination or (f) a change in the state of science that changes equipoise or has other significant impact on the relevance of the question under study.

The NICHD Director retains responsibility for all NICHD-funded research. The NICHD Director receives the DSMB’s recommendations on whether Network studies should be continued or terminated and can make an independent decision on how to proceed. The NICHD Director can override the decisions of the PFDN Steering Committee when it is in the strategic interest of the NIH/NICHD, human subject protection, and/or dependent on funding availability.

The Scientific Process

Each PFDN study is developed by a protocol committee in an iterative process from concept, through mini and ultimately full protocol with an analysis plan. SC approval is required at each stage, ensuring high quality and impactful initiatives with consensus throughout the protocol development process. The protocols are reviewed and approved by the AB and DSMB (Figures 1 and 2). While new concepts can be presented by investigators at any time, at the beginning of each cycle, the PFDN sites and/or outside investigators present concept proposals to the SC.

Figure 2. Process of Trial Development.

• Phase 1. Protocol Development

After group discussion, the SC votes on which proposals to advance to an index study. A supermajority (i.e., 6/9 or 7/10) vote is needed for a concept to be approved for further advancement as PFDN experience showed that concepts with only simple majority ultimately failed to progress to final protocol. A protocol committee, with chair and vice chair is then formed for approved concept proposals with one member from each PFDN site, a DCC representative, NICHD project scientist and a DCC research coordinator to progressively develop the concept into a mini-protocol and then if approved, to full protocol. Consultants with content expertise outside the PFDN may be included within the protocol committee.

At each stage, the protocol committee develops all parts of the trial including aims, methods, and analysis plan in greater detail, typically through in-depth discussions during virtual meetings. Investigators are intimately involved in product selection (as indicated), considerations for involving industry, and identifying specific procedures and techniques used during the trial. Simultaneously, members of the protocol committee work with the budget and consent committees to develop a budget and an informed consent document, respectively. Supermajority votes by the SC are required for the concept proposal to advance to the mini-protocol stage of development and then again to full protocol. The Advisory Board reviews studies at the mini-protocol stage to provide scientific feedback. Trial protocols are reviewed and approved by the DSMB before enrollment begins.

• Phase 2. Protocol Implementation

Research study coordinators are critical partners in protocol development and implementation. Once a concept has evolved into a SC/AB/DSMB-approved final protocol (Figure 1), the DCC coordinates with members of the protocol team and research coordinators develop a detailed manual of procedures (MOP) and case report forms (CRFs) including screening forms, baseline measures, operative or other treatment-related forms, and follow-up forms. In developing these forms, protocol teams strive to learn from prior experience using similar validated outcomes measures while also evaluating the need for additional new or improved measures or outcomes. Data collection has evolved with advancing technology and data are now collected through electronic CRFs. Once data collection forms are final, the DCC develops and tests electronic data capture and capitation systems before full implementation.

If the protocol requires an Investigational New Drug (IND) or Investigational Device Exemption (IDE) approval, the IND process with the FDA is initiated once the full protocol and consent is approved and the clinicaltrials.gov registration is started. In early Network studies, the IND/IDE holder was the NICHD; currently, the lead site investigator that introduced the concept holds the IDE/IND. All clinical trials are posted to the clinicaltrials.gov website by the DCC and IRB approval is obtained before enrollment begins. In keeping with NIH policies, all PFDN studies since 2018 have a single IRB of record. Preparation for study implementation includes a structured process of training site investigators and research coordinators. The sessions are coordinated by the DCC, in conjunction with the protocol committee chair, and other subject matter experts.

As a protocol (Figure 2) is being developed, investigators may also propose supplementary studies which address a different aspect of the index study and which require the collection of additional data. Ancillary analyses use existing data from an index or supplementary study. They cannot overlap with planned primary or secondary analyses in the protocol.

The PFDN has also leveraged expertise in qualitative and measurement science to make substantive contributions to developing new patient reported measures that are actively utilized.^18–23 Ongoing work is being performed to determine the clinical meaningfulness from the patient perspective of adverse events (AEs) and adverse symptoms related to surgical interventions.^24,25 Finally, to further ensure PFDN trials are patient-centric, a Consent Committee reviews all study consents, vetting them with non-investigators and lay persons to confirm that they are understandable to patients.

Protocol teams consider barriers and opportunity to engage and enroll women who have been marginalized due to current inequitable systems and infrastructure in society. Acknowledging this historical inequity, the PFDN now requires a section in protocols that includes discussion of the anticipated study population demographics at each site and explanation regarding plans to over-recruit under-represented populations. In addition to race and ethnicity, other socioeconomic markers will be considered to better capture characteristics of PFDN study populations and may include zip code, sexual orientation, non-English speaking, and other markers of socioeconomic status such as rural populations. Protocols will also describe if proposed demographic categories will have sufficient enrollment to have statistical power to detect differences between groups and to avoid masking potential health inequities. The Diversity, Equity, and Inclusion (DEI) Committee reviews all protocols for these components during protocol development and annually reviews actual versus anticipated enrollment of ongoing trials.

Assessment of Complications

For clinical trials, 3 entities review AEs: the Medical Safety Monitor (MSM), DSMB, and an AE Adjudication Committee. The MSM is part of the DCC and provides independent review of serious AEs (SAEs) and AEs to ensure data are complete and consistent before the events are reported to the DSMB, NIH, and the Food and Drug Administration (FDA) as appropriate. While the DSMB is primarily concerned with ensuring participant safety, the focus of the AE Adjudication Committee is to achieve consistency in AE reporting across clinical trials and clinical centers. This committee was formed to address the challenge of consistently classifying AEs based on terminology, relationship to the study interventions, severity, impact and outcome. In the case of AEs which are related to each other, these are condensed into the final diagnosis (for example; individual AEs of “chest pain,” “ED visit,” “ICU admission” and “Cardiac catheterization” and “Myocardial Infarction” would be condensed into the latter). For severity grading, PFDN uses the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), and surgical complications are additionally assigned a Clavien-Dindo classification.²⁶

The AE Adjudication Committee, comprised of three clinical center investigators, reviews AEs reported for all studies. Classifications of AE severity and relationship as assigned by site PI and AE Adjudication committee members are compared; in the case of discrepancy, consensus among committee members is reached through discussion at standing meetings. Through this process, the committee identifies areas where specific guidance to clinical center investigators would facilitate consistency in reporting. For example, during one trial, the committee recognized the need for greater consistency in the evaluation of severity for granulation tissue. CTCAE lacked specific criteria for granulation tissue, therefore, the AE Adjudication Committee developed definitions for mild, moderate, and severe events. These processes have achieved the goal of increased consistency in AE severity grading and relationship assessments, as evidenced by the current high degree of agreement between adjudicators and site clinicians.

Standardization and Training

During study design discussions, PFDN investigators consider regional and specialty variation in assessments and interventions with an overarching goal of producing generalizable and reproducible trial results. Consensus is sought for decisions regarding how to characterize a population, conduct an intervention, or collect an outcome. The investigators intentionally standardize interventions. As an example, in the CARE trial (Table 2), the intervention under study was the Burch colposuspension at the time of sacrocolpopexy.³ The protocol committee standardized the Burch technique while allowing variation in suture and mesh types for the sacral colpopexy. Similarly, for OPTIMAL,¹⁰ SUPeR¹⁴ and ASPIRe,¹⁶ the elements of each apical suspension were standardized but the technique for colporrhaphy was not, increasing generalizability. This decision did introduce limitations to subsequent ancillary studies exploring the benefit of anterior and posterior colporrhaphy in transvaginal prolapse procedures; however, it also enabled investigators to understand the variability in surgeons’ practices regarding the choice (ranging from 0–100%) to incorporate anterior colporrhaphy in prolapse repairs.^27,28

Surgeon / Interventionist Certification

To reduce bias related to surgical experience and to attempt to minimize known complications, surgeons were required to have adequate experience with all procedures being performed in a trial. (Table 3) The surgeons were also required to watch training videos and attest to their review of the elements of the procedure. The PI at each site was responsible for proctoring surgeons on new investigational procedures, such as placement of transvaginal mesh, and reviewing outcomes for AEs before certifying that the surgeons met eligibility criteria. This standardization may have played a role in the low number of mesh complication outcomes noted in the SUPeR trial.¹⁴

Table 3.

Surgeon Certification Process for the Two Surgical Procedures in the SUPeR Study¹⁴

For TVH/ULS Certification
(1) All surgeons viewed a DVD illustrating essential components of the uterosacral vault suspension technique. Training video can be found at: (https://www.pfdnetwork.org/ResearchStudies/ActiveStudies/SUPeR/PhysicianTrainingVideos.aspx)
(2) All certified surgeons performed a minimum of 20 vaginal hysterectomies, 20 uterosacral procedures, with at least 5 of these apical procedures in the 12 mo before beginning participant enrollment.
For Uphold certification
(1) All surgeons viewed a DVD illustrating essential components of the Uphold technique. Training video can be found at: (https://www.pfdnetwork.org/ResearchStudies/ActiveStudies/SUPeR/PhysicianTrainingVideos.aspx)
(2) All certified surgeons performed a minimum of 20 sacrospinous ligament dissections with performance of at least 10 anterior vaginal dissections to the sacrospinous ligament and at least 10 Capio suture applications
(3) Performance of, or had received hands on proctoring on at least 5 Uphold LITE procedures for uterovaginal prolapse or cuff-vaginal prolapse.
(4) Before signing off on certification for each site’s surgeon, the site PI reviewed these 5 cases for any Uphold LITE procedure related complications and could request additional procedures if skills were not well demonstrated.

PI, principal investigator.

Lessons Learned:

Minimum datasets and participant burden

Consistent use of standardized outcomes has enabled secondary studies of combined data across similar, well characterized study populations. This is exemplified by the longitudinal observation of participants of the CARE, OPUS, OPTIMAL and SUPER trials. Analyses of 709 participants in these prolapse surgical trials identified 5 clusters of women who experienced different degrees of surgical success and failure based upon anatomy and symptoms.²⁹ This analysis provocatively highlights the limitation of anatomic definitions of surgical success and validates clinicians’ observations that asymptomatic prolapse recurrence may be an acceptable outcome for some patients. The nuanced report of outcomes may be useful in counseling women and has prompted discussion of refining definitions of success after POP surgery.³⁰

During protocol development, investigators reconcile the desire for comprehensive collection of outcomes and participant burden, using a guiding principle of avoiding data collection without a plan for analysis. The inclusion and frequency of questionnaire collection is evaluated by the expected contribution of new information to the field. While the PFDN seeks to compare trial outcomes to those in the published literature, the investigators also critically review whether the questionnaires serve their intended purpose of reporting patient-centered outcomes without creating undue burden. At times, a need for developing and validating an instrument may arise. While planning an FI trial, the protocol team became aware of the lack of patient-centered outcomes in the existing condition-specific instruments. To fill this gap, the network developed and validated a new instrument, the Accidental Bowel Leakage Evaluation (ABLE) questionnaire to ascertain type, severity and bother of bowel leakage, and ancillary bowel symptoms, including predictability, awareness, leakage control, emptying disorders, and discomfort.^18,31,

Addressing Barriers to Participant Representation and Mitigating Attrition in Longitudinal Trials

The focus on participant retention begins with study design (feasibility) and recruitment strategies. Trial consents and inclusion criteria emphasize a participant’s availability and willingness to provide outcomes and attend study visits throughout the study duration. Limiting in-person study visits helped to minimize missing data and participant burden. The PFDN routinely administers questionnaires to participants on tablet computers in the clinic or via emailed secure survey links; this strategy reduces missing data, staff effort and data entry errors. For the NOTABLe trial of posterior tibial nerve stimulation (PTNS) for FI, the PFDN developed and validated a PFDN Bowel Diary mobile application to improve the ease of collecting bowel diary data.^32,33

These efforts positioned the network well to pivot from in person study visits during the COVID-19 pandemic to remote, web-based ascertainment of patient reported outcomes. This effective, retention-focused strategy enabled critical ongoing follow-up of participants in the SUPeR, ASPIRe and MUSA trials.^14,16,17 The PFDN has found that ubiquitous access to smart phones, tablets or computers has enabled strong trial retention with high levels of participant satisfaction. The investigators anticipate that this change in research practice will be maintained.

Reliable, Reproducible Measurements in PFD Research

The PFDN was established within 5 years of the multi-society endorsement (International Continence Society, October, 1995; American Urogynecologic Society, January, 1996; Society of Gynecologic Surgeons, March, 1996) of a standardized approach to quantifying pelvic organ prolapse.³⁴ An important, humbling, early discovery by investigators was the variability in technique employed by research teams when obtaining pelvic organ prolapse quantification (POPQ) measurements and conducting reduction stress urinary incontinence testing. Survey results highlighted the variability of POPQ examination techniques by and within sites (empty or full bladder, use of speculum, lithotomy versus standing). Similarly, apical support for reduction stress testing was variably achieved using the posterior blade of a speculum, ring forceps, pessary, fingers and swabs, in either lithotomy or standing position. After conducting studies that assessed the reliability of POPQ and stress testing, the network subsequently standardized techniques for POPQ, empty bladder stress testing, and retrograde fill cough stress tests. Ensuring that POPQ measures were being measured with fidelity led to research efforts supporting the concept that pelvic organ prolapse, including “failure” of surgical repair, is not necessarily dichotomous.²⁹ This has led to ongoing work exploring how to best capture POP outcomes that are meaningful to patients. PFDN trials of surgical POP repair have used composite primary outcome measures which include patient-reported outcomes in addition to anatomic and “objective” measures in order to include the participant perspective on treatment success (OPTIMAL, SUPeR and ASPIRe trials).^10,14,16

The PFDN investigators determined that standardization of urodynamic technique and technology is important. Specifically, PFDN research demonstrated that significant variability existed in intravesical pressures recorded by microtip and water-based systems indicating they are not interchangeable.³⁵

Other successful examples of staff training to optimize a standardized approach include interpretation of bladder diaries and implementation of behavioral therapy interventions for UI, POP and FI.^7,13,10,12 In the absence of an established ‘gold standard’ for behavioral interventions, protocol teams focused on developing a reproducible protocol based upon a literature review.^7,12,13 The standardized approaches included elements of pelvic muscle strengthening and training, bladder retraining and delayed voiding, urgency suppression and stress strategies based on the best available evidence for the targeted symptom. One of the challenges encountered was limiting the unconscious deviation from protocol by clinically active interventionists who might incorporate their own preferred strategies in patient counselling and pelvic muscle training. To ensure fidelity with study treatment implementation, the protocol team incorporated a quality control plan including audits of interventional audio recordings.^12,13 Protocol deviations identified through the recordings were brought to the interventionists’ attention for remediation.

Not all efforts at central training to teach a new skill, or train staff for data acquisition, were successful at achieving consistency. Incorporating a mechanism for quality assessments has proven to be an important step for our multicenter research network. This was specifically important for pelvic imaging data, which are not routinely collected for clinical care. In the Childbirth and Pelvic Symptoms (CAPS) Imaging study, despite in-person centralized training to standardize image interpretation, there was poor reproducibility for soft-tissue parameters on dynamic MRI pelvic measurements between readings performed at the sites compared to central, expert review.³⁶ This informed the exclusive use of centralized reading of dynamic MRI pelvic measures in the subsequent DEMAND study.^37,38

The Effort Needed for Effective Masking

Masking of participants, interventionists, and assessors was frequently utilized to minimize real or perceived bias in trials. This is a resource intensive effort that requires extensive collaboration with institutional billing departments (to block or divert surgical, anesthesia and pathology bills), surgical services administration (to create research instrument trays that include equipment for two different procedures), nursing services (to agree not to ask or share detailed information about the impending procedure), and creative use of staff. For trials studying prolapse interventions, potential ascertainment bias has been minimized by ensuring that the study surgeon or interventionist is not involved in post-treatment anatomic outcome assessments and the assessor is masked to group assignment. All patient-reported outcome measures are administered prior to clinical assessments to minimize any bias that may occur due to clinical findings.

Institutional Review Boards (IRBs) at each PFDN site provided approval for sham incisions in the OPUS⁸ trial and over-encapsulation of medications in the ABC⁹ and CAPABLe¹² trials to ensure patient and provider masking. One of our most challenging masking efforts was in the SUPeR¹⁴ trial, a comparative effectiveness trial of two surgical strategies for uterovaginal prolapse with assignment to hysterectomy or mesh hysteropexy. To limit confounding associated with purported adverse effects of mesh or of hysterectomy, participants agreed not to learn their group assignment for up to 5 years (unless unmasking was required for medical necessity). The protocol team extensively considered all opportunities in routine clinical care at which the participant might be unmasked and developed a plan to mitigate the risks. This included issuing an operating room (OR) reservation request for research surgery, attention to pre-op nursing interactions and the “time out” OR process, standardized documentation in the operative report, and study payment of the pathology bill to avoid references to a uterine specimen assessment on insurance claim forms. Participants were encouraged to see the study team for any gynecologic problems or evaluations during the study. Seventy percent of participants remaining masked through 5 years.³⁹

Internal and External Collaboration

The PFDN has reached out for collaboration with other NIH institutes including the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute on Aging (NIA), investigators from other departments within PFDN member sites (such as gastroenterology, radiology, geriatrics and basic science), ancillary recruiting sites and industry (Boston Scientific). Resources are leveraged to fulfill the research question at hand. The NIDDK sponsored Urinary Incontinence Treatment Network (UITN) was formed with many of the same member sites as vanguard PFDN sites (4 first cycle sites, Magee-Womens Research Institute, Pittsburgh, PA, Loyola University Chicago, University of Alabama at Birmingham, and University of Utah, and 2 more second cycle sites, UTSW and UCSD), so it was natural for the two networks to collaborate on study launch timing and content.⁴⁰ Although this did not result in any joint clinical trials, it allowed for open communication on study launches and potential for ancillary site participation. The Office of Research on Women’s Health (ORWH) has also partnered with the PFDN with adjunctive funding for clinical trials.

The PFDN made early commitments to incorporate translational elements to studies. Examples include the MRI imaging done in the CAPS and SUPeR trial participants, urinary biomarker studies in the ROSETTA trial, as well as the investigations of the microbiome in the ABC, CAPABLe and ESTEEM trial participants, and urgency urinary incontinence genetic polymorphism analyses.^41–47 These critical supplementary studies require special expertise within the PFDN sites provided by investigators from other departments. For example, radiologists were recruited from the PFDN sites to perform the imaging of SUPeR participants per the DEMAND protocol, and expertise was brought on from the University of Pittsburgh and University of Alabama at Birmingham (UAB) sites to partner in protocol development and analyze the images. Laboratories at UAB, Colorado State, and University of New Mexico conducted microbiome and metabolome analyses of biospecimens from CAPABLe and ESTEEM trial participants.

Ancillary sites are solicited to expedite recruitment for certain trials. Use of ancillary sites has been in effect since PFDN’s inception, when additional sites were recruited for the PFDN’s initial trial, the CARE trial, and later for the ROSETTA and MUSA trials. The PI from the ancillary site participates in all the meetings associated with that study or trial, including study design (if the ancillary site is recruited early enough), progress reports, safety and quality assessments, as well as writing groups for dissemination of findings.

Reflections - Missed Opportunities

Most investigations did not involve innovative or new procedures. Although some PFDN investigators from various cycles have been surgical innovators and early adopters, early studies for newer procedures were not pursued within the network until the third and fourth five-year cycles. For example, vaginal mesh procedures were introduced in the United States in 2005. The SUPeR vaginal mesh hysteropexy versus native tissue repair trial concept was presented in June 2011 and the first patient randomized in April, 2013. Three-year follow-up data, published in September, 2019, showed that the two procedures were similar in anatomic and functional outcomes. However, in a parallel but unlinked process, vaginal mesh kits were taken off the United States market in 2019. The importance of longer-term outcomes assessments became evident when 5-year SUPeR data published in 2021 showed that women undergoing mesh hysteropexy had an 18% improved composite cure rate compared to total vaginal hysterectomy with repairs.³⁹ Earlier collaboration with industry on various innovative procedures could have provided level I evidence based on unbiased outcome assessments that may have influenced shared decision making and availability of vaginal mesh for prolapse. The PFDN, in collaboration with industry, has the capability, resources, and expertise to carry out well-designed 522 post-market surveillance studies and/or RCTs on surgical devices.

Steps Forward and Summary

The PFDN remains a successful research consortium for reporting long-term outcomes of randomized gynecologic surgical trials resulting in evidence-based clinical care information. The PFDN evolved to recognize and develop mechanisms to improve PFD research and address limitations in research processes. Translational research continues to be a strength and focus of the network and it is typical for primary research protocols to include supplementary translational aims. This has ranged from conducting work on vaginal, gut, and urinary microbiome, bowel metabolome, anatomic mechanisms of POP, to on-going trans-disciplinary collaboration in regenerative techniques. A Biorepository Committee was developed to establish a process and to help oversee the handling and management of specimens obtained through PFDN studies.

Although PFDN trials (Table 2) attempted to be inclusive, diversity and inclusiveness goals were not achieved.⁴⁸ In the most recent cycle, 2022–2027, the PFDN is focusing on diversity, equity and inclusion of enrolled study populations. A DEI Committee was formed in 2023 and is tasked with overseeing changes in the protocol development process to improve the transparency and expectations of diverse recruitment in future trials. The committee will closely track study enrollment to evaluate the success of these efforts. Further, it is recognized that study design and results obtained may not be generalizable to urogynecologists and their patients in private practice or in smaller/rural community centers. Perhaps over time this may change as increased outside proposals for studies are received.

In summary, pelvic floor disorder research gaps have been actively addressed by the PFDN, resulting in improvement and refinement of research approaches and methodology widely used by PFD researchers. With reflection on lessons learned and missed opportunities, the PFDN infrastructure and commitment to meaningful research on pelvic floor disorders is an important contribution to evidence for PFD care. The strong infrastructure and engagement of the entire network team are at the core of its success. Patient participants and research coordinators are critical to these efforts. The PFDN continues to evolve and improve in response to the changing needs of affected patients, research, and communities.

Simply Stated:

This report summarizes the initiation, evolution, and growth of the Eunice Kennedy Shriver NICHD Pelvic Floor Disorders Network (PFDN). The PFDN has been instrumental in enhancing evidence-based research in Urogynecology since 2001 through design and implementation of landmark trials which guide clinical care for women with pelvic floor disorders. Complementing the clinical efforts are translational studies which have contributed to our understanding of the development of these conditions. Through continued tax-payer support these research efforts have advanced women’s health and quality of life.

Why This Matters:

This history is important for researchers, trainees and providers of urogynecologic care so that these efforts continue to grow and further help us offer the best evidence-based approaches to the care of women with PFDs and ultimately lead to efforts that may help prevent these conditions.