Dr Leonie Hunt, Australia

Australia has an independent regulatory system, which covers premarket assessment, pharmacovigilance programmes, the use of standards, enforcement of GMP requirements, a register of approved goods, and clinical trials. Independent expert advisory committees have been used extensively to provide guidance for decisions. For medicine regulations, there are the Australian Guidelines for Registration of Drugs. International guidelines are adopted whenever appropriate.

Fixed-combination products are important tools in therapeutic regimes. They may have a number of potential advantages over single therapies, including greater effectiveness, improved safety profile and simpler therapy. However, there are also potential disadvantages. As the formulation is fixed, doses cannot be easily adjusted to meet the needs of individual patients. For patients who are well controlled by single therapies, fixed combinations may give unnecessary exposure to a second medicine. Furthermore, there are additional adverse events. Therefore, justification is needed for each particular fixed-combination product, and the development of such a product should address the issues of the benefit and risk of the combination. Justification should take into account effectiveness, safety and improved compliance.

Fixed combinations must be of acceptable quality and logical combination. Moreover, the effect of interactions, within or outside the combination, on the pharmacodynamics and pharmacokinetics, should be investigated. In Australia, it is generally recommended that new combinations should be used as an add-on to single therapy, unless it can be demonstrated that use of the combination drug as first-line treatment is optimal. The minimum effective dose and maximal dose response should be established for the drugs used alone and in combination. The efficacy of the combination should be compared with the effective doses of the medicines alone, other reference therapies, and placebo. Finally, animal studies should have been performed and human data are required, for the medicines administered singly and in combination, to ensure safety.

In summary, fixed-dose combinations offer potential advantages to patients but are not always appropriate or rational. Careful selection of the medicines to be used, and assessment of use of the combination, are required to maximize the benefit.