title: Asthma management: the challenge of equivalence.
abstract: Increasing prevalence and severity of asthma worldwide encourage the development of new antiasthmatic drugs, alternative treatment regimens and improved formulations of established drugs. Whereas the efficacy of new chemical entities (NCEs) is usually demonstrated by superiority over placebo or a subtherapeutic dose of the active drug, equivalence concepts have to be used in the following situations: the need to replace chlorofluorocarbon (CFC) propellants for inhalative asthma medications by suitable alternatives, and the need to demonstrate that an alternative treatment regimen is not clinically inferior to an established reference treatment. To cover both situations, the recent ICH guidance on biostatistics clearly distinguishes between two-sided equivalence trials and one-sided non-inferiority trials. In this context, non-inferiority always means "not inferior by a clinically relevant amount". After having confirmed non-inferiority, superiority of the alternative test treatment over the reference treatment can additionally be tested without the need to adjust the significance level. The definition of equivalence acceptance limits becomes crucial, particularly in studies conducted in the flat range of the dose-response curve of inhaled steroids. In order to assess the non-inferiority of steroid sparing add-on treatments we propose a one-sided test based on post-/pre-ratios which have substantially reduced coefficients of variation compared to the post-treatment values themselves. The non-inferiority acceptance limit of 0.90 - as opposed to 0.80 in bioequivalence assessment - reflects clinically irrelevant changes of lung function variables. The proposed methodology is illustrated by 2 examples from randomized, double-blind, parallel-group studies comparing inhaled steroid plus theophylline versus doubling the steroid dose in asthmatics who are symptomatic on low-dose inhaled steroid.
authors.affiliation: Byk Gulden Pharmaceuticals, Konstanz, Germany.
authors.forename: V W
authors.initials: VW
authors.lastname: Steinijans
authors.forename: M
authors.initials: M
authors.lastname: Neuhäuser
authors.forename: T
authors.initials: T
authors.lastname: Hummel
authors.forename: S
authors.initials: S
authors.lastname: Leichtl
authors.forename: F
authors.initials: F
authors.lastname: Rathgeb
authors.forename: A
authors.initials: A
authors.lastname: Keller
mesh_terms: D000280:Administration, Inhalation; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001249:Asthma / Q000188:drug therapy*; D017402:Chlorofluorocarbons; D016001:Confidence Intervals; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006801:Humans; D009330:Nebulizers and Vaporizers / Q000592:standards; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design; D018401:Sample Size; D013256:Steroids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013806:Theophylline / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency
chemical_list: D018927:Anti-Asthmatic Agents; D017402:Chlorofluorocarbons; D013256:Steroids; D013806:Theophylline