ASTHMA MANAGEMENT - THE CHALLENGE OF EQUIVALENCE

Increasing prevalence and severity of asthma worldwide encourage the d evelopment of new antiasthmatic drugs, alternative treatment regimens and improved formulations of established drugs. Whereas the efficacy o f 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 repl ace chlorofluorocarbon (CFC) propellants for inhalative asthma medicat ions by suitable alternatives, and the need to demonstrate that an alt ernative treatment regimen is not clinically inferior to an establishe d reference treatment. To cover both situations, the recent ICH guidan ce on biostatistics clearly distinguishes between two-sided equivalenc e trials and one-sided non-inferiority trials. In this context, non-in feriority always means ''not inferior by a clinically relevant amount' '. After having confirmed non-inferiority, superiority of the alternat ive test treatment over the reference treatment can additionally be te sted without the need to adjust the significance level. The definition of equivalence acceptance limits becomes crucial, particularly in stu dies conducted in the flat range of the dose-response curve of inhaled steroids. In order to assess the non-inferiority of steroid sparing a dd-on treatments we propose a one-sided test based on post-/pre-ratios which have substantially reduced coefficients of variation compared t o the post-treatment values themselves. The non-inferiority acceptance limit of 0.90 - as opposed to 0.80 in bioequivalence assessment - ref lects clinically irrelevant changes of lung function variables. The pr oposed methodology is illustrated by 2 examples from randomized, doubl e-blind, parallel-group studies comparing inhaled steroid plus theophy lline versus doubling the steroid dose in asthmatics who are symptomat ic on low-dose inhaled steroid.