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Education And Debate

Trials to assess equivalence: the importance of rigorous methods

BMJ 1996; 313 doi: (Published 06 July 1996) Cite this as: BMJ 1996;313:36
  1. B Jones, professor of medical statisticsa,
  2. P Jarvis, senior lecturer in medical statisticsa,
  3. J A Lewis, visiting professor in medical statisticsa,
  4. A F Ebbutt, director of European clinical statisticsb
  1. a Department of Medical Statistics, School of Computing Sciences, De Montfort University, Leicester LE1 9BH
  2. b Glaxo Wellcome Ltd, Greenford, Middlesex UB6 0HE
  1. Correspondence to: Professor J A Lewis, Medicines Control Agency, London SW8 5NQ.

    The aim of an equivalence trial is to show the therapeutic equivalence of two treatments, usually a new drug under development and an existing drug for the same disease used as a standard active comparator. Unfortunately the principles that govern the design, conduct, and analysis of equivalence trials are not as well understood as they should be. Consequently such trials often include too few patients or have intrinsic design biases which tend towards the conclusion of no difference. In addition the application of hypothesis testing in analysing and interpreting data from such trials sometimes compounds the drawing of inappropriate conclusions, and the inclusion and exclusion of patients from analysis may be poorly managed.

    The design of equivalence trials should mirror that of earlier successful trials of the active comparator as closely as possible. Patient losses and other deviations from the protocol should be minimised; analysis strategies to deal with unavoidable problems should not centre on an “intention to treat” analysis but should seek to show the similarity of results from a range of approaches. Analysis should be based on confidence intervals, and this also carries implications for the estimation of the required numbers of patients at the design stage.

    The gold standard in clinical research is the randomised placebo controlled double blind clinical trial. This design is favoured for confirmatory trials carried out as part of the phase III development of new medicines. Because of the number and range of medicines already available, however, new medicines are increasingly being developed for indications in which a placebo control group would be unethical. In such situations one obvious solution is to use as an active comparator an existing drug already licensed and regularly used for the indications in question. Some authors have questioned whether placebo controlled trials are used excessively and unethically, …

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