Editorial: The Ethics of Recent Gout Trials
Authors: Robert H. Shmerling
Journal: Arthritis & Rheumatology (2016)

Over the last decade, we have seen important advances in our understanding of gout and its therapy, including the development of several new drugs and new guidelines to encourage optimal management 1-5. A dramatic increase in the number of clinical trials enrolling thousands of patients with gout has allowed us to understand the important risks and benefits of these new drugs. As important as these recent trials have been and as important as it is to develop new medications for the unmet needs in the care of patients with gout, the design of some recent trials raises fundamental ethical concerns. Well-designed (and ethical) clinical trials exploring the efficacy of a new medication for gout would treat the comparator group with the type of care we would provide in our own practices. Furthermore, enrolled patients should not receive care that we (rheumatologists) would consider suboptimal or inappropriate. According to a paraphrasing of the "Golden Rule," we should expect the comparison group to receive care that we would want if we were enrolled in the study. These are not new concepts. Years ago, trials in RA often included a placebo arm in which patients received little or no active treatment. As our understanding of the capacity of RA to cause early and irreversible joint damage evolved, rheumatologists balked at the idea of enrolling patients with RA into trials that allowed assignment of study subjects to a placebo arm for prolonged periods of time 6, 7. Such trials might be useful to fully understand the impact of a new treatment, but, for the most part, ethical concerns rightly put an end to placebo treatment of patients with RA (although trials in which methotrexate is underdosed in the comparator arm continue to appear). Despite this history, recent trials in gout in which newly developed drugs are compared utilize designs that raise similar—and additional—ethical issues. The most common design is treatment of patients with a fixed dose of allopurinol 8, 9. Up-titration was not allowed in these trials; the justification was that a fixed daily dose of 300 mg is common (or "standard") in clinical practice, that there is a lack of clinical trials confirming the safety of up-titration based on serum urate levels, and that such dose changes would compromise blinding. These explanations are not compelling and violate a central tenet of urate-lowering therapy: treat to target. Labeling this arm of the study design "standard" because prescribing physicians (especially primary care physicians) often recommend allopurinol at a dosage of 300 mg/day or less does not justify its use as a fixed dose in a clinical trial. Treatment practice that is common should not be confused with care that is good; ideally, "standard of care" should evolve from expert recommendations for optimal care rather than from the recommendations of practitioners with less experience. Additionally, if a rheumatologist is involved in a clinical trial involving patients with gout, his or her conception of "standard of care" certainly should prevail. This is especially important if we are in agreement that treating to target is important, and that common practice (e.g., fixed dosing of allopurinol in the range of 200–300 mg/day) is also suboptimal 10-12. Many or most patients treated with fixed-dose allopurinol in this range will not reach the target reduction in serum uric acid. The challenge of encouraging prescribers of allopurinol to start low, up-titrate, and treat to target is well documented; however, just because it is challenging does not justify enrolling patients to receive care or to continue care that we know is ineffective. That is, no rheumatologist should deprive a patient of optimal care in order to enroll that patient in a drug trial. At a minimum, clinical research should incorporate valid science, social benefit, and a favorable risk-to-benefit ratio for the study subjects 13. Comparing patients receiving a new drug with those receiving underdosed allopurinol would appear to fail to meet the last 2 of these goals: the social benefit of determining whether a new drug is better than an underdosed older drug is questionable at best. In fact, the social benefit of any trial depends in part on the magnitude of the "unmet need"; however, this need may be small, because simple up-titration of allopurinol would often be effective for patients in whom uric acid suppression was inadequate while they were receiving lower doses. Finally, subjecting study subjects to known undertreatment adds unnecessary risk, especially because information regarding the potential benefit of up-titration is readily available. Another principle of ethics that is relevant to clinical trial design is the appropriateness of comparing treatments considered to be in equipoise; that is, there should be a well-reasoned presumption that active treatment in each arm of the trial might be equally effective 14. However, we set the bar too low and may violate the principle of equipoise if one of those treatment arms is known to undertreat many or most patients 8-12. Clearly, the outcome of such a trial is biased to favor a new drug if the comparator group is undertreated. As I reviewed posters and listened to presentations at the 2015 American College of Rheumatology (ACR) meeting in San Francisco, a new crop of gout trials caught my eye. This time the active comparators were lesinurad or arhalofenate in combination with allopurinol 15, 16. Again, the allopurinol dosage was generally in the range of 300 mg/day (or 200 mg/day for patients with renal dysfunction), and rather than up-titrating the allopurinol as recommended by current guidelines 4 and as we would typically recommend in our practices, an additional, new medication (with the attendant risks of polypharmacy and uncertain toxicities) was administered to the study subjects. In at least one trial 16, study subjects received allopurinol therapy without prophylaxis (and suffered through the predictable increase in the number of gout flares), while other subjects received treatment with a placebo. The most common barriers to appropriate dosing of allopurinol are concerns about serious allopurinol hypersensitivity reactions 17, 18 (especially among patients with renal dysfunction) and a lack of appreciation of the importance of treating to target. The 2012 ACR guidelines for the management of gout and a number of recent studies 4, 19, 20 demonstrate the safety of starting with low doses and gradually up-titrating allopurinol, even in the face of renal impairment. Well before the new guidelines were published, however, the importance of treating to target had been widely endorsed and encouraged 21-23. Calls to provide prescribers with better education and making urate monitoring and suppression a goal of quality-improvement programs have become commonplace. Although the best studies regarding the safety of up-titrating allopurinol in a patient with renal impairment have been published only recently, the case for underdosing allopurinol in study subjects with normal renal function seems even less defensible. Why have trials in which allopurinol is underdosed proliferated? Perhaps it is because, in contrast to RA, gout is considered to be a benign disease, and a (short) period of undertreatment may have no long-lasting impact. Clearly, RA has more potential for irreversible joint damage and functional impairment than does gout, and rheumatologists are probably more forgiving of the "sin" of undertreating gout than undertreating RA. However, I suspect that patients who cannot walk during a gout flare or who are admitted to the hospital with polyarticular disease and fever would see things differently; a similar and compelling case has been made for the treatment of chemotherapy-induced nausea 24. On the other hand, perhaps we are giving up (too soon) on the idea that prescribers of allopurinol will ever routinely optimize dosing in clinical practice. Of course, there is a financial incentive for pharmaceutical companies to maximize the chances that a new drug will appear to be effective; underdosing allopurinol does just that but at the cost of biasing the trial and subjecting some study participants to suboptimal therapy. Whatever the explanation, I am hopeful that researchers, pharmaceutical companies, and institutional review boards will put an end to clinical trials in gout that are designed with arms that include suboptimal treatment. These trials may subject patients to unnecessary suffering and risk and raise important ethical concerns that go well beyond differences of opinion regarding ideal trial design or methodology. Recent gout trials have treated study subjects in ways we would not recommend for our own patients. Considering this fact, we should be reluctant to refer our patients to such trials. Certainly, if I were eligible to be a study subject, I would not consider enrolling in a study in which I might be randomized to receive a placebo or a dose of allopurinol that has a high failure rate, unless there was a clear contraindication to up-titration. Rheumatologists should demand better—and more ethical—gout trials that 1) limit enrollment to study subjects with disease that is refractory to appropriately dosed conventional therapies, 2) eliminate placebo arms, 3) routinely provide treatment for flare prophylaxis, and 4) allow appropriate up-titration of urate-lowering treatment in comparator arms. Such trials may be more challenging and costly to implement, but they will be better for study subjects, and the information provided will be more valuable. This applies not only to gout, of course; RA trials (some of which underdose methotrexate in the comparator arm) and trials of treatment for other rheumatic disease should also be careful to avoid undertreating comparator groups. Finally, we badly need rigorously designed trials that evaluate the safety and efficacy of the treat-to-target strategy; although some rheumatologists may not think this is necessary, confirming (or refuting) the advisability of this approach is necessary to address remaining doubt. As I compare the clinical trials of RA from several decades ago with the current generation of gout trials, it seems clear that some lessons must be relearned. I am grateful to C. Ronald MacKenzie, MD, for reviewing the manuscript and providing insightful suggestions. Dr. Shmerling drafted the article, revised it critically for important intellectual content, and approved the final version to be published.