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Improved Trials of Rheumatology Drugs?
In a study by Rebecca Rothwell and colleagues, which appears in Arthritis & Rheumatology, possible considerations of non-inferiority (NI) trials assessing treatment effects in RA are discussed.
The authors determined that an NI trial comparing a novel treatment to an anti-TNF agent using the symptomatic endpoint of ACR20 response can feasibly provide evidence of a treatment effect, with a 12% absolute difference as one possible appropriate NI margin. For mean change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI), margins in the range of 0.10 to 0.12 were considered reasonable based on the estimated historical treatment effects, resulting in required sample sizes in the range of those required for the ACR20 endpoint for 80% power. In evaluating radiographic progression, an appropriate margin and the corresponding feasibility of the trial is dependent on the selected active control and the expected variability in progression.
In conclusion, pursuing phase 3, active-controlled NI trials was recommended in drug development in RA.
The use of conventional placebo-controlled trials in RA has several limitations. It appears that NI comparisons to anti-TNF agents are feasible for symptomatic and functional endpoints to assess drug effects in RA. Active-controlled NI trials with justified NI margins can provide persuasive evidence of treatment effects on symptomatic, functional, and radiographic endpoints without the need for subject exposure to ineffective, non-standard-of-care treatments. Randomized, active-controlled NI trials can also provide reliable long-term safety information — which obviously has implications for evaluating novel immunosuppressant agents.
One limitation of NI trials is that some investigators in smaller centers may consider the required sample size for an adequately powered study very large. Other important endpoints will also need to be considered and investigated in future studies.
Siamak Moghadam-Kia, MD, MPH, is assistant professor of medicine and staff rheumatologist at the University of Pittsburgh Medical Center in Pittsburgh, PA.
An abstract of the study here.
