Challenges in Conducting Trials in Nephrology: Conclusions From KDIGO

Tejas P. Desai, MD


September 27, 2017

Nephrologists around the world are intimately familiar with the lack of randomized, controlled clinical trials (RCTs) in nephrology. Indeed, an increasingly larger portion of providers is relying on nonrandomized and biased trial data to make daily clinical decisions. Clinicians, who have waited years for trialists to execute RCTs, are beginning to accept the notion that perfection is the enemy of good. They believe that nonrandomized trials, with their known biases and flaws, are good enough for nephrologists and our patients. Thankfully, there are some trialists who refuse to accept this notion and are actively working to change the way in which evidence-based data are generated.

The Kidney Disease: Improving Global Outcomes (KDIGO) group convened a meeting of stakeholders in September 2016 to identify challenges and make recommendations to improve trial data in nephrology.[1] Their conclusions were made public nearly 8 months later and are briefly reported below.

Four Domains for Successful RCT Execution

The multinational participants of this KDIGO conference were from the European Union, United Kingdom, North America, and Australia. From the start, these trialists recognized four domains that must be considered for the successful execution of a randomized trial: (1) randomization of a sufficient number of patients, (2) adherence to the allocated treatment arms, (3) ascertainment of relevant study outcomes, and (4) appropriate statistical analyses. Whereas the participants considered all four domains equally important, a plurality of readers felt differently.

The randomization of a sufficient number of patients was the most concerning to our readers. The KDIGO participants suggested a nonspecific broad set of inclusion criteria but specifically suggested implementing criteria to exclude participants who were predicted to be (1) nonadherent to the treatment protocol or (2) unlikely to survive the duration of the trial. The participants cleverly suggested using the "prerandomization run-in" period to identify patients whose adherence would jeopardize the power of the study. Therefore, the run-in period would now serve two purposes: its original purpose of establishing a common baseline for all patients, and a new purpose of spotlighting those who would likely alter the results of the study owing to nonmedical reasons.

Our readers chose statistical analyses as the least likely domain to affect randomized trial execution. Nonetheless, the participants suggested tempering one's a priori hypothesis of treatment effect. Lowering one's expectations of treatment effect can help design a more modest clinical trial that has a greater chance of being executed and completed.

In addition, our overreliance on subgroup analyses should be mitigated. All randomized trials should focus on the primary outcomes, even if those outcomes are negative. A concerted effort should be made to focus on negative primary outcomes when the data suggest positive subgroup or secondary outcomes.

Selecting the appropriate outcomes received the second highest vote by our readers. Admittedly, I chose this outcome as the main obstacle to completing randomized trials, after repeated frustration with albuminuria reduction as an accurate predictor of clinically relevant endpoints. The participants strongly favor the use of changes in the estimated glomerular filtration rate (eGFR) as a clinically relevant outcome. Even in such trials where disease-specific markers are available, the participants intimate that both the markers and eGFR should be concomitantly assessed. Unlike this author, the participants have not taken a hardline approach against the use of albuminuria, and don't offer clear guidelines on when and how this endpoint should be elevated to primary outcome status.

Finally, the participants suggest that adherence to the treatment arms can be improved by first eliminating those patients who are predicted to be nonadherent. For the patients who remain in the study, their individual adherence can be improved by minimizing the number of clinic visits and laboratory testing. Both can be achieved if clinical trials are designed to collect and analyze a minimum number of biological tests.

Tell us what you think: Which of the four domains do you feel contribute to the lack of RCTs in nephrology? What did the participants in the KDIGO meeting miss that you feel is an important domain to consider? Use the comments section below to share your thoughts.

Follow Tejas P. Desai, MD, on Twitter: @nephondemand

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