Raising the standard of trial registration,conduct,and reporting

Evidence-based medicine can be defined as the conscientious, explicit, judicious, and reasonable use of modern, best evidence in making decisions about the care of individual patients. ¹ A randomized controlled trial (RCT) serves as the gold standard platform for evaluating the effectiveness of interventions, thereby generating the highest quality evidence to inform practice. ² However, the ability of investigators to conduct RCTs is increasingly challenged by escalating costs, resource constraints, and ethical and governance compliance requirements. These barriers have translated into a 25% reduction in the number of clinical trial applications in recent years. ³ Nephrology as a discipline is particularly vulnerable as it has consistently recorded the lowest number of trial publications (with suboptimal methodological quality) compared to any other medical disciplines. ^{4 –6} These deficits can be clearly observed by reviewing guidelines published to inform clinical decision-making. For example, the latest International Society for Peritoneal Dialysis guideline on catheter-related infection included 19 recommendations or suggestions, of which only two were supported by high-certainty evidence. ⁷ Recommendations on peritoneal dialysis (PD) training, which is a fundamental foundation to enable safe and effective PD, are based on low-certainty evidence at best, ⁸ such that a high-quality RCT is desperately needed to guide practice.

Ljungman et al. ⁹ report findings from their Peritonitis Prevention Study (PEPS), which examined an important question on the effect of implementing protocol-driven retraining to prevent peritonitis. This was an investigator-initiated, multicenter, open-label, parallel design RCT of incident adult PD patients recruited from 57 centers across 8 countries. Of the 671 randomized patients, 340 were allocated to the retraining intervention and underwent rigorous competency tests encompassing written and practical components (average duration 2–2.5 h/session), followed by further training if prespecified target scores were not reached. Compared with controls, patients receiving protocol-driven retraining experienced comparable peritonitis-free survival rates (hazard ratio (HR) 0.92, 95% confidence interval 0.71–1.19, p = 0.52 during the study period; HR 0.87, 95% CI 0.63–1.21, p = 0.41 during the first year). The proportions of patients experiencing peritonitis were also similar (37% in the control group vs. 30% in the intervention group). The findings from this study are highly relevant to the PD community as they evaluate an important intervention strategy targeting PD-related infection, which is considered by patients and caregivers to be the top-rated, most critically important outcome in PD. ^{10 –12} Moreover, the study enrolled a large sample of incident PD patients from 57 centers across eight countries, which increases the generalizability of its findings. However, the strength of evidence was constrained by suboptimal recruitment (89% of target), a high dropout rate that was higher in the intervention group (45% in the retraining group; 35% in the control group at 1 year, and 80% and 74% at trial completion), open-label design, selection of a low-risk population (as evidenced by low control group infection rates), and risk of contamination whereby participating PD units concurrently cared for patients allocated to both the intervention group and the control group. From the trial conduct perspective, delayed trial registration until after patients had been enrolled and nonadherence to intention to treat analysis were important pitfalls. Unfortunately, these limitations highlight the challenges that confront contemporary researchers and consumers of research.

The conduct of a trial requires a well-established research infrastructure and funding that are often beyond the reach of researchers or clinicians who wish to conduct trials. Despite their struggles, investigators of the PEPS trial invested their best efforts to complete the trial as they had originally intended including expansion of sites to enhance recruitment. Rather than glossing over their limitations, the PEPS investigators took the opportunity to explicitly discuss valuable lessons learned during trial conduct that are broadly applicable to the research community. In fact, these matters need to be recognized and rectified to improve future trial quality and outcome reports. Peritoneal Dialysis International has an important part to play in achieving this goal.

Currently, it is estimated that up to 85% of medical research is wasted, which translates to approximately US$170 billion per year. ¹³ The international research community has been trying to address this serious issue by making considerable efforts to deliver research that is meaningful, relevant, and efficient for end users as well as by enforcing adherence to international standards by trial investigators to enable incorporation of generated evidence. PD peritonitis studied by the PEPS trial investigators is one of the core outcome domains identified by the Standardized Outcomes in Nephrology–Peritoneal Dialysis (SONG-PD), defined as outcomes critically important to all stakeholder groups that must be reported in all PD trials. ^{10 –12} However, despite these positives, the trial’s impact was weakened by limited funding and resource capacity which in turn compromised adherence to international standards.

In 2005, the International Committee of Medical Journal Editors (ICMJE) recommended prospective registration of all interventional clinical trials that began after July 1, 2005, to improve methodological standards and to promote transparency. These recommendations have been endorsed by the US Food and Drug Administration Amendment Act of 2007, World Health Organization, and further enabled by establishment of ClinicalTrials.gov in 2008. ^14,15 The principal purpose of trial registration and results submission is to publicly document medical research to fulfil ethical obligations to participants and the research community, provide information to potential participants and referring clinicians, reduce publication and outcome reporting biases by confirming adherence to a prespecified trial protocol, prevent research duplication, and increase transparency to help editors and users of medical literature to better understand the context of study results. ^15,16 Disappointingly, adherence to reporting guidelines and clinical trial registration policies have been inconsistent across all medical disciplines. ^{17 –20} A recent review of adherence to the ICMJE prospective registration policy of 486 trials published in high-impact specialty society journals identified that 10% of trials were unregistered and that 23% of the registered trials were actually registered retrospectively. ²⁰ Unregistered trials were more likely to report positive findings compared to registered trials (89% vs. 64%; relative risk 1.38, 95% CI 1.20–1.58, p = 0.004). ²⁰ Delayed trial registration, such as occurred with the PEPS trial, has been shown to affect up to one-third of trials registered with the ClinicalTrials.gov. ¹⁵ These failures to follow recommended standards undermine research integrity and directly contribute to research waste. Immediate changes in values and cultures are required by all, including researchers, journals, research institutions, and funders.

At Peritoneal Dialysis International, we have stated our commitment to ICMJE guidelines in submission guidelines. This created a dilemma when delayed registration of the PEPS trial was identified because of conflicting ethical obligations to publish and disseminate the findings of important research conducted in patients receiving PD and to ensure that such research meets an acceptable standard with respect to registration, conduct, and reporting. We subsequently audited recently published trials in Peritoneal Dialysis International and found that not all had been prospectively registered. A decision was therefore made to publish the PEPS trial because its findings and experiences were felt to be valuable. However, in future, the reviewers and editors of the Peritoneal Dialysis International will strictly ensure that all accepted trial manuscripts fully comply with the ICMJE guidelines to improve the transparency, accessibility, standards, and impact of health research.