title: Adjusting for covariates in non-inferiority studies with margins defined as risk differences.
abstract: Adjusting for covariates makes efficient use of data and can improve the precision of study results or even reduce sample sizes. There is no easy way to adjust for covariates in a non-inferiority study for which the margin is defined as a risk difference. Adjustment is straightforward on the logit scale, but reviews of clinical studies suggest that the analysis is more often conducted on the more interpretable risk-difference scale. We examined four methods that allow for adjustment on the risk-difference scale: stratified analysis with Cochran-Mantel-Haenszel (CMH) weights, binomial regression with an identity link, the use of a Taylor approximation to convert results from the logit to the risk-difference scale and converting the risk-difference margin to the odds-ratio scale. These methods were compared using simulated data based on trials in HIV. We found that the CMH had the best trade-off between increased efficiency in the presence of predictive covariates and problems in analysis at extreme response rates. These results were shared with regulatory agencies in Europe and the USA, and the advice received is described.
authors.affiliation: GlaxoSmithKline, Uxbridge, UK.
authors.forename: Khadeeja
authors.initials: K
authors.lastname: Mohamed
authors.forename: Andrew
authors.initials: A
authors.lastname: Embleton
authors.forename: Robert L
authors.initials: RL
authors.lastname: Cuffe
mesh_terms: D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D004335:Drug and Narcotic Control / Q000706:statistics & numerical data*; D005060:Europe; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D038622:Internationality; D016015:Logistic Models; D015233:Models, Statistical; D016017:Odds Ratio; D010919:Placebos; D011760:Pyrrolidinones / Q000009:adverse effects / Q000627:therapeutic use; D000068898:Raltegravir Potassium; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000706:statistics & numerical data*; D012107:Research Design / Q000706:statistics & numerical data*; D018570:Risk Assessment / Q000706:statistics & numerical data; D018401:Sample Size; D012680:Sensitivity and Specificity; D016896:Treatment Outcome; D014481:United States
chemical_list: D019380:Anti-HIV Agents; D010919:Placebos; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium