History and Future of Multi-Institutional Clinical Trials in Urinary Incontinence

Urinary incontinence (UI) is a common symptom that primarily affects females but can also be present in males. Worsening of UI symptom ultimately will adversely affect the quality of life of the patient. The symptom of UI sometimes can be confirmed on a physical examination or urodynamic testing. On occasion, however, the symptom of UI cannot be objectively verified. Treatment algorithms for UI involve the ability to differentiate between stress UI (SUI) and urge UI (UUI). It is assumed that the ideal outcome of UI treatment is a highly satisfied patient who is continent.

Given this brief introduction, it would appear that evaluation and management of UI is straightforward and without too many unknowns, but this is not true. Many unanswered questions remain today:

• What are the specific pathophysiologic etiologies for SUI and UUI?

• Which objective tests can be performed to help clinicians diagnose and treat UI and, furthermore, prognosticate outcomes of these treatments?

• Which treatments for UI offer the most durable long-term outcome with the greatest patient satisfaction?

These questions should be tackled with the modern scientific tool of multi-institutional clinical trials (MICTs), which can provide the highest level of evidence-based medicine. While clinical trials may answer certain questions, the more exciting scenario is that of unanticipated findings that spur further hypotheses. Through MICTs, new or improved treatments will be developed, with the discarding of less effective treatments along the way. Ultimately, the beneficiary of this process will be the UI sufferer.

In 1999, the National Institutes of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health issued a request for application to assemble a consortium of clinical sites to perform clinical trials addressing the most pressing issues related to UI treatment. This request for application was called the Urinary Incontinence Treatment Network (UITN). Ultimately, nine clinical sites and one biostatistical coordinating center were selected to form the UITN. The UITN is not dissimilar, for example, to the National Cancer Institute Cancer Cooperative Groups, in which effective treatments for cancer are studied through MICTs. The UITN accomplished four “index” MICTs between 2001 and 2010. The first trial, Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr), compared outcomes of Burch colposuspension against those of autologous fascial pubovaginal slings for SUI treatment. The second trial, Behavior Enhances Drug Reduction of Incontinence (BEDRI), compared outcomes of behavior intervention plus oral antimuscarinics against those of oral antimuscarinics alone for UUI treatment. The third trial, Trial of Mid-Urethral Slings (TOMUS), compared outcomes of retropubic against those of transobturator midurethral polypropylene slings. The last trial, Value of Urodynamic Evaluation (ValUE), compared outcomes in SUI patients who had basic office evaluations against those who had urodynamics to assess the utility of preoperative urodynamics. The results of three of these index MICTs have been published [1–3], with the results from ValUE pending.

The trials also spawned several “secondary” analyses of the datasets generated by these trials. These secondary analyses have generated many new questions, including the following:

• Can the utility of urodynamics be demonstrated in an MICT?

• What is the ideal outcome variable(s) for UI trials?

• Why do objective outcomes not match subjective outcomes?

• What constitutes health-seeking behavior in patients with UI?

• How do we best quantitate the cognitive-behavioral components that contribute to UI?

• How can we better phenotype the UI patient using objective markers?

• What is the best marker for UI severity?

• What is the best prognosticator for outcomes from different treatments?

• What measures can be instituted to prevent treatment side effects?

• What are the costs patients are willing to spend on treatment of UI?

These further questions should form the basis for future MICTs.

The UITN will be “decommissioned” in 2012. However, this should not be the end for MICTs in UI. The hot button topics in biomedical research today—genetics, personalized medicine, biomarkers, stem cells, tissue regeneration, bioinformatics, and nanotechnology—all should be advanced and refined in the field of UI through MICT mechanisms. Perhaps the ability to perform MICTs should not depend so heavily on governmental initiatives. Potential clinical sites for future MICTs can be found easily by examining the membership of professional medical associations such as the Society for Urodynamics and Female Urology and the American Urogynecologic Society. The leadership of these two organizations could collaborate to spearhead the organization, formation, and execution of future MICTs in UI. Of course, even the best collaborative efforts will fail if insufficient funding exists. A combination of funding sources—federal funds, private foundations, donations, and pharmaceutical/medical device companies—will be required.

As we look toward the future, there will be an explosion of the proportion of the US population older than 65 years of age, thus significantly increasing the number of patients afflicted by UI. The costs incurred by evaluation and treatment of UI will therefore become an economic issue. Therefore, finding the best treatments for UI must be balanced against higher costs. However, performing appropriate and well-designed MICTs can show which treatments provide the best value and are the most cost-effective.