title: Non-inferiority tests for anti-infective drugs using control group quantiles.
abstract: In testing for non-inferiority of anti-infective drugs, the primary endpoint is often the difference in the proportion of failures between the test and control group at a landmark time. The landmark time is chosen to approximately correspond to the qth historic quantile of the control group, and the non-inferiority margin is selected to be reasonable for the target level q. For designing these studies, a troubling issue is that the landmark time must be pre-specified, but there is no guarantee that the proportion of control failures at the landmark time will be close to the target level q. If the landmark time is far from the target control quantile, then the pre-specified non-inferiority margin may not longer be reasonable. Exact variable margin tests have been developed by Röhmel and Kieser to address this problem, but these tests can have poor power if the observed control failure rate at the landmark time is far from its historic value.
  
  
  
  We develop a new variable margin non-inferiority test where we continue sampling until a pre-specified proportion of failures, q, have occurred in the control group, where q is the target quantile level. The test does not require any assumptions on the failure time distributions, and hence, no knowledge of the true [Formula: see text] control quantile for the study is needed.
  
  
  
  Our new test is exact and has power comparable to (or greater than) its competitors when the true control quantile from the study equals (or differs moderately from) its historic value. Our nivm R package performs the test and gives confidence intervals on the difference in failure rates at the true target control quantile. The tests can be applied to time to cure or other numeric variables as well.
  
  
  
  A substantial proportion of new anti-infective drugs being developed use non-inferiority tests in their development, and typically, a pre-specified landmark time and its associated difference margin are set at the design stage to match a specific target control quantile. If through changing standard of care or selection of a different population the target quantile for the control group changes from its historic value, then the appropriateness of the pre-specified margin at the landmark time may be questionable. Our proposed test avoids this problem by sampling until a pre-specified proportion of the controls have failed.
authors.affiliation: Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, Rockville, MD, USA mfay@niaid.nih.gov.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fay
authors.affiliation: Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, Rockville, MD, USA.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Follmann
mesh_terms: D000890:Anti-Infective Agents / Q000627:therapeutic use*; D035061:Control Groups; D000074099:Equivalence Trials as Topic; D006801:Humans; D015233:Models, Statistical; D012107:Research Design; D013997:Time Factors; D017211:Treatment Failure
chemical_list: D000890:Anti-Infective Agents
keywords: Difference in proportions; exact test; non-inferiority margin; variable margin