Some Thoughts on Challenges for Noninferiority Study Designs
- PDF / 418,386 Bytes
- 8 Pages / 602.986 x 782.986 pts Page_size
- 68 Downloads / 150 Views
Some Thoughts on Challenges for Noninferiority Study Designs
Drug Information Journal 46(4) 420-427 ª The Author(s) 2012 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0092861512445310 http://dij.sagepub.com
David L. DeMets, PhD1, and Lawrence Friedman, MD2
Abstract New interventions that may have some advantage over standard treatments by being less invasive, less toxic, or less costly are often compared to standard therapy. Noninferiority trials aim to demonstrate that the new intervention is almost as good as, or even better than, the standard. A commonly used paradigm makes numerous assumptions to obtain a statistical and clinical margin of noninferiority, many of which are difficult to prove and may be based on subjective assessments. We discuss these assumptions and give examples where they are not met. Regardless of the methods that are used, the margin of noninferiority must reflect what patients and health care providers are willing to balance for the possible benefits of the new intervention for fewer adverse events or less invasiveness or cost. Keywords noninferiority trial, superiority trial, trial design, meta-analysis
Introduction Traditionally, most clinical trials were superiority trials. That is, they were designed to demonstrate that a new treatment or intervention was better than some standard, either an existing treatment or placebo. However, recently, many trials have a different goal1,2 since there is effective standard therapy, making it neither ethical nor of medical interest to show that a new intervention is better than a placebo. The new interventions may have little or no superiority to standard therapy with respect to clinical outcomes but still may be of interest because they are less toxic, more easily administered, cheaper, or have some other feature of value to patients. Here, the trial aims to demonstrate that the new intervention is not worse than the standard treatment by some predefined margin of noninferiority. In this article, we assume that all trials are conducted with a background of usual care. A key consideration is that the standard therapy is known to be better than no treatment or placebo by some amount. If the new intervention is not worse than the standard, one would want to conclude, therefore, that if it had been compared against a placebo, it too would have beaten the placebo. As discussed below, however, unless clear guidelines are established in the design, implementation, and analysis of noninferiority trials, such a conclusion is far from certain. To illustrate the concepts around noninferiority designs, consider the trials represented in Figure 1, showing relative risk estimates for the intervention effect with 95% confidence
intervals.3 The vertical line on the right specifies the amount of worse effect of the intervention compared relative to the control that could be tolerated, defined as d, and the other line represents a relative risk of unity, or no intervention difference. Trial A is everyone’s hope that the new interven
Data Loading...
