title: Testing superiority at interim analyses in a non-inferiority trial.
abstract: Shift in research and development strategy from developing follow-on or 'me-too' drugs to differentiated medical products with potentially better efficacy than the standard of care (e.g., first-in-class, best-in-class, and bio-betters) highlights the scientific and commercial interests in establishing superiority even when a non-inferiority design, adequately powered for a pre-specified non-inferiority margin, is appropriate for various reasons. In this paper, we propose a group sequential design to test superiority at interim analyses in a non-inferiority trial. We will test superiority at the interim analyses using conventional group sequential methods, and we may stop the study because of better efficacy. If the study fails to establish superior efficacy at the interim and final analyses, we will test the primary non-inferiority hypothesis at the final analysis at the nominal level without alpha adjustment. Whereas superiority/non-inferiority testing no longer has the hierarchical structure in which the rejection region for testing superiority is a subset of that for testing non-inferiority, the impact of repeated superiority tests on the false positive rate and statistical power for the primary non-inferiority test at the final analysis is essentially ignorable. For the commonly used O'Brien-Fleming type alpha-spending function, we show that the impact is extremely small based upon Brownian motion boundary-crossing properties. Numerical evaluation further supports the conclusion for other alpha-spending functions with a substantial amount of alpha being spent on the interim superiority tests. We use a clinical trial example to illustrate the proposed design.
authors.affiliation: Merck Research Laboratories, Rahway, NJ, PA, USA. Joshua_chen@merck.com
authors.forename: Y H Joshua
authors.initials: YH
authors.lastname: Chen
authors.forename: Cong
authors.initials: C
authors.lastname: Chen
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics / Q000627:therapeutic use; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D048588:Benzoxazines / Q000493:pharmacokinetics / Q000627:therapeutic use; D057186:Comparative Effectiveness Research / Q000379:methods* / Q000592:standards / Q000706:statistics & numerical data; D003521:Cyclopropanes; D003627:Data Interpretation, Statistical; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D011760:Pyrrolidinones / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068898:Raltegravir Potassium; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000592:standards / Q000706:statistics & numerical data; D012136:Respiratory Syncytial Viruses / Q000187:drug effects; D059039:Standard of Care; D013810:Therapeutic Equivalency
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D061067:Antibodies, Monoclonal, Humanized; D000998:Antiviral Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; C506968:motavizumab; C098320:efavirenz