Magnani CJ, Steinberg JR, Harmange CI et al: Clinical trial outcomes in urology: assessing early discontinuation, results reporting, and publication in ClinicalTrials.Gov registrations 2007–2019. J Urol 2021; doi: 101097JU0000000e000001432.

Clinical trials provide the key mechanism for furthering the evidence base for patient care, yet they require substantial financial and professional resources. To serve the scientific community, trials must first complete and then disseminate their findings through publication or online trial registries. Clinicaltrials.gov represents one of the largest international repositories of clinical trial data, and in an effort to improve accountability, U.S. federal law has mandated registration of most phase 2 to phase 4 interventional studies since 2007.¹ Because aggregate analysis of the registry is challenging, prior investigations of clinical trials in urology have been limited to small samples or have focused on specific diseases.^2–6 In our recent study, we provide the largest and most comprehensive characterization to date of the urology clinical trial landscape.⁷ We assessed the role of sponsorship and subspecialty, captured time trends and compared trial features. Our findings show significant room for improvement in how urology as a field performs in carrying out clinical trials.

Using a combination of programmatic and manual methods,⁷ we identified interventional studies in urology (8,636) registered between 2007 and 2019 on ClinicalTrials.gov, and assigned them to subspecialties: andrology, endourology, female, general, oncology, pediatric or renal transplant. The registry contained information on key trial features (sponsors, use of a data monitoring committee, early termination, causes of termination etc) as well as reported results for completed trials, while associated publications were captured via linkage to the PubMed® MEDLINE® bibliographic database.

More than half of urology trials (51.9%) were in oncology, and the majority of trials were sponsored by academic institutions (53.1%), followed by industry (37.1%) and government sources (9.8%). Compared to industry, government-sponsored trials were more focused on oncology, pediatrics and endourology, with fewer in andrology or general urology. Academic-sponsored trials had the smallest contingent in oncology, with larger proportions in endourology and female urology (see table). Urology trials increased at a 4.1% annual growth rate, driven entirely by academic-sponsored trials (+9.4%), while government and industry saw no significant change. Oncology trials increased (+4.9%), as did endourology (+14.6%), female (+7.5%), general urology (+3.8%) and pediatrics (+2.8%). Growth in North America (+3.1%) and Europe (+5.5%) was outpaced by other regions (+7.1%, fig. 1).

Figure 1. Clinical trials in urology over time. A, number of trials. B, number of trials by sponsor. C, number of trials by subspecialty. D, number of trials by geographic region.

Figure 2. Cumulative incidence of early discontinuation, results reporting and publication. A, early discontinuation results by sponsor; log-rank test p=0.007. B, early discontinuation results by specialty; log-rank test p <0.001. C, results reported by sponsor; log-rank test p <0.001. D, results reported by specialty; log-rank test p <0.001. E, results published by sponsor; log-rank test p=0.056. F, results published by specialty; log-rank test p <0.001.

A total of 3,541 (41.0%) trials were completed, while 999 (11.6%) were discontinued. Of completed trials, dissemination of results was poor, occurring in only 40.2% of trials. Only a quarter (26.9%) reported results to the registry, while a fifth (21.6%) were published, and only 8.3% did both. Kaplan-Meier analysis demonstrated significant unadjusted differences by sponsor for early discontinuation (p=0.007) and results reporting (p <0.001), and subspecialty had significant unadjusted differences for all 3 primary outcomes (p <0.001, fig. 2). Reason for discontinuation differed by sponsor (p <0.001) but not subspecialty (p=0.2), with participant accrual by far the most common (39%) reason across sponsors. Industry next cited sponsor/business decision (18%), while academic and government-sponsored trials reported budget/staff shortages (11% and 10%, respectively).

Figure 3. Association of sponsor and subspecialty with early discontinuation (A), results reporting (B) and publication (C).

In adjusted models accounting for features of trial design like type of intervention, government-sponsored trials were the most likely to perform well. Compared to industry, they were 38% less likely to discontinue early and most likely to report (adjusted OR 1.72) and publish (aOR 1.89) within 3 years of completion. Academic-sponsored trials were 19% less likely than industry to discontinue and more likely to publish (aOR 1.72), but were the least likely to report results to the registry (aOR 0.65). Most subspecialties performed similarly relative to oncology. However, endourology was twice as likely to discontinue, general urology was more likely to report results (aOR 1.54) and andrology was less likely to publish (aOR 0.53, fig. 3).

As clinical trials represent enormous investments of resources on behalf of investigators and patient participation, it is important to understand if they deliver through trial completion and sharing findings. While it is encouraging that early discontinuation appears to occur in only a minority of trials, it is extremely worrisome that so few urology trials disseminate results, and urgent efforts at improvement are necessary. The identified association of sponsorship with trial outcomes provides insight into areas of potential improvement and optimization of trial success, given that sponsor incentives and processes for choosing trials differ. Industry is subject to market incentives that likely underlie an increased risk of discontinuation. Challenges known to impact academic-sponsored trials include inadequate research staffing and a higher number of new, inexperienced investigators who may struggle to comply with the requirements and procedures for registry reporting, unlike industry, where structured support and familiarity with the process are the norm, or government sponsorship, which often requires investigators to have proven track records and entails additional oversight.⁸

Because most urology trials are sponsored at academic centers with institutional funds, they provide a particular opportunity for urologists to engage and help improve trial completion and reporting. Academic centers could consider pooling resources to form “core facilities” available to investigators, hoping to optimize trials for success. These centralized resources could include training opportunities, facilitated mentorship between new and experienced investigators, statistical resources, and professional staffing familiar with registry compliance requirements ready to assist with results submission. Just as journals have required prospective registration of trials as a condition for article submission, they can encourage or require results reporting to registries at the time of publication. Given that accrual presented the leading cause of discontinuation and was especially pronounced among academic-sponsored trials, resources should be devoted to understanding the underlying reasons for these failures. For example by identifying whether enrollment and exclusion criteria are too restrictive or if eligible patients are simply not being referred to trials, targeted interventions in the form of resources to help with recruitment or trial design can be effectively deployed. Urology has long been a field of innovators; by coming together, we can pave the way to improve trial transparency and enhance the quality of ongoing and future research.