The conduct of clinical trials poses ethical questions for any medical condition, and gout is no exception, including some of its own peculiarities. In 2016, Robert H. Shmerling, MD, of Harvard Medical School at Boston, published an editorial that laid out ethical considerations for running gout clinical trials.

Shmerling advocated for limiting trial enrollment to patients with gout that is refractory to appropriately dosed conventional therapies, eliminating placebo arms, providing routine anti-inflammatory prophylaxis to reduce gout flares, and allowing up-titration of urate-lowering treatments in comparator arms.

But will Shmerling’s four recommendations hold up in the current therapeutic landscape and into the future?

In a presentation at the Gout Hyperuricemia and Crystal Associated Disease Network Annual Research Symposium (G-CAN) 2025, Lisa Stamp, MBChB, PhD, professor of rheumatology at the University of Otago, Christchurch, New Zealand, and her colleagues reviewed and updated his work.

“What we wanted to start thinking about was whether these recommendations are fit for 2025, 2026, and beyond,” she said.

Limit Trials to Patients With Refractory Gout?

Stamp noted that there are different definitions of refractory gout, as well as limitations to making it the sole eligibility criteria for clinical studies. “If we limit enrollment to those with refractory gout, then we’re making a lot of assumptions about what conventional therapies are doing and that no other urate-lowering therapy could be as good as those. But there might be other benefits to new urate-lowering therapies. They might have less frequent dosing. They might have fewer adverse events. They might have fewer gout flares on initiation, for example. And we’ll miss that if we limit it to people who are refractory,” she said during her presentation. She also said that restricting a trial to patients with difficult-to-treat gout may reduce generalizability of findings to the more general population.

“Where we landed is that inclusion criteria for participants in any clinical trial of urate-lowering therapy need to be aligned with the primary research aim, the goals of treatment, and the potential benefits and harms of the agent, rather than simply restricting it to those who have refractory disease,” she said.

When Is It Acceptable to Eliminate Placebo Arms?

Stamp said that placebo arms make sense in short-duration phase 1 and 2 studies, in which the aim is to determine dosing and look for safety signals, “but I think for longer-duration trials and phase 3 and 4 trials, the use of placebo presents greater ethical challenges for us.” The 2024 Declaration of Helsinki called for placebo-controlled trials only when there is no proven effective intervention or if there is a compelling and scientifically sound reason for its inclusion. Given the proven efficacy of allopurinol, febuxostat, and probenecid, these drugs should be used as comparators in clinical trials, Stamp said, but added that there were potential exceptions such as trials that include a standard treatment with an add-on therapy.

Joint Decisions on Anti-inflammatory Prophylaxis

Anti-inflammatory prophylaxis to reduce gout flares is recommended by the American College of Rheumatology and the European Alliance of Associations for Rheumatology, but there are downsides, including adverse events, drug-drug interactions, and the potential for gout flares after cessation of prophylaxis. “So I think it should be mandated that we offer anti-inflammatory prophylaxis to patients, but this really should be a joint decision between the healthcare provider and the participant and that respects the participant’s autonomy and safeguards participants’ well-being by balancing the risks and benefits of the available agent for that particular individual. Unless the trial is specifically designed to investigate the effects of anti-inflammatory prophylaxis, there’s no obvious reason why they shouldn’t be eligible to participate in a urate-lowering therapy trial,” Stamp said.

Make Sure Comparator Drugs’ Dosing Is Optimal

Shmerling argued that patients in standard-of-care arms were receiving doses of allopurinol that many rheumatologists would consider suboptimal, which introduced a bias into the trials and made it more likely that novel therapies would be found to be superior. Stamp referenced the FACT trial from 2006, which found febuxostat to be superior to a fixed 300-mg dose of allopurinol, while a 2022 trial found no difference between febuxostat and allopurinol doses that were allowed to increase to a maximum of 800 mg.

Although a low dose of allopurinol is widely considered to be standard of care for gout, “in actual fact, it’s probably not best practice because we know that it’s recognized in all the gout guidelines that we should start allopurinol at a low dose and gradually dose titrate to a target urate [level], and we do that to decrease the risk of adverse effects and gout flares in the short term and then in the long term by achieving target urate [level] to improve patient-reported outcomes such as flares and tophi. We need to think about how we define what our standard-of-care arms should be and transfer that to what best practice is,” Stamp said.

She also pointed out gaps in Shmerling’s recommendations, suggesting that patients with gout should have a predetermined gout care plan because it can be hard to see a provider quickly following a flare, and rapid treatment is advantageous. “Everyone should have a plan and a supply of flare therapy,” Stamp said. When exiting a trial, patients should have a defined management plan for ongoing urate-lowering treatment and be given a supply of flare therapy.

Historic Control Individuals and Other Practical Considerations

In the Q&A session after the presentation, Youssef Roman, PharmD, PhD, an associate professor of pharmacy practice and administrative sciences at Idaho State University in Pocatello, Idaho, wondered if real-world data or historic control individuals could be used in the design of clinical trials. “Everybody gets active treatment, and nobody gets placebo. Are we there yet?” he asked. 

Stamp said that such an approach is inappropriate for phase 1 or phase 2 trials but could have a place in phase 3 or phase 4 studies. “The bottom line is everyone needs to receive active treatment. [Historic control individuals] is one way to solve that problem,” she said. 

Kenneth G. Saag, MD, professor of medicine at The University of Alabama at Birmingham, applauded the ethical considerations brought up by Stamp but wondered about practical considerations within the regulatory environment. “Regulators generally are not going to accept noninferiority studies, and the cost of doing active comparator studies for superiority is astronomical. Moreover, if you don’t look at refractory gout and you look at just standard gout and you get a label for that, how are you going to sell it initially, even if you think it’s safe?” he said.

Stamp responded that his point underlines the tension with pharma-driven drug development. “We want new therapies for people who haven’t responded to what we’ve got, but they’re often more expensive. Proving that the cost benefit is greater than something like allopurinol is a very real challenge, but maybe the regulators need to be thinking about what’s ethical as well,” she said.

Stamp did not make any financial disclosures. Roman and Saag could not be reached for financial disclosures. 

Jim Kling is a writer based in Bellingham, Washington.