Asthma therapy: No evidence of an additional benefit of fixed combinations

In some patients with asthma, treatment with inhaled corticosteroids (ICS) is insufficient. These patients may profit from a combination therapy of ICS and inhaled long-acting beta-2-receptor agonists (LABA). The 2 drug classes can be administered separately by 2 inhalers. Moreover, a device in which both drugs are administered at a fixed-dose ratio has been available for some years. However, patients do not profit more from these fixed combinations administered by a single inhaler than from the individual combination therapy drugs administered by separate inhalers, as IQWiG has now determined. The final report, published on 4 November 2008, therefore confirms the results of a benefit assessment already presented in 2007. The Institute has extended and updated the previous assessment as new drug combinations have been launched onto the market in the meantime, and an older combination therapy has been granted an extended approval.

Foster, Inuvair, and SMART regimen included in the assessment

IQWiG determined the benefit for patients by assessing, among other things, whether the treatments reduced the severity of asthma symptoms and the rate of exacerbations, hospital admissions, and outpatient visits. It was also assessed whether one therapy option caused fewer adverse events than the other. Outcomes also included health-related quality of life, physical capacity, and restrictions in activities of daily living.

The IQWiG report commissioned by the German Federal Joint Committee and completed in April 2007 only compared the 2 fixed combinations of budesonide/formoterol (tradename: Symbicort) and fluticasone/salmeterol (trade names: Viani and Atmadisc) versus each other and versus the individual combination therapy drugs administered by separate inhalers.

The supplementary commission also included the first-time assessment of the later approved combination of beclomethasone dipropionate/formoterol (tradenames: Foster and Inuvair), as well as budesonide/formoterol (Symbicort) for maintenance and reliever therapy (tradename: SMART). When IQWiG started work on the first assessment in July 2005, this combination was approved for maintenance therapy only. As in the first benefit assessment, the supplementary commission not only compared the 2 different types of administration of the drugs (fixed combination vs. individual drugs), but also the benefit of the various fixed combinations with each other.

Fixed combinations not superior to administration of individual drugs in separate inhalers

The researchers included a total of 16 studies in the benefit assessment, and concluded that there was no evidence of an additional benefit of one of the 2 types of administration. In fact, if the same inhalation systems were used, the studies available provided similar results overall for the fixed combinations budesonide/formoterol and fluticasone/salmeterol versus the individual combination therapy drugs administered by separate inhalers. Studies on the new combination of beclomethasone dipropionate/formoterol versus the individual drugs are so far lacking. This applies both to adolescents and adults as well as to children.

Likewise, in the comparison of fixed combination therapies with each other, in adolescents and adults there are neither indications nor evidence that patients profit more from one therapy option than from another (with one exception).

The exception is budesonide/formoterol for maintenance and reliever therapy (SMART; manufacturer: AstraZeneca); i.e., in the application for which the manufacturer was granted extended approval. For this therapy, the results indicate that adults experience fewer severe exacerbations than with salmeterol/fluticasone (manufacturer: GlaxoSmithKline). However, the Institute views this finding with reservations, as it is unclear whether all studies conducted so far were available for the benefit assessment. Currently unavailable data could call the results of the assessment into question.
"Severe exacerbations” was the only outcome for which an advantage for budesonide/formoterol (SMART) was indicated. For all other outcomes, for example, asthma symptoms, quality of life, or adverse events, the data already published did not show differences compared with the fixed combination of fluticasone/salmeterol.

In children, no comparisons between the different fixed combinations were identified.

Not all manufacturers cooperative

In order to include preferably all available study results in the benefit assessment, IQWiG not only searched literature databases, but also public and company-owned study registries. In addition, manufacturers were asked to provide data on comparative clinical studies whose results were not or not fully publicly available. Both the companies GlaxoSmithKline (salmeterol/fluticasone) and Asche Chiesi (beclomethasone dipropionate/formoterol) made an agreement with IQWiG at the beginning of the assessment, in which they agreed to disclose all studies they had conducted on the drugs under investigation and to provide previously unpublished data. This was linked to the permission to publish the data provided in the report. All data subsequently requested by IQWiG were provided by the 2 companies.

In contrast, AstraZeneca refused to sign an agreement on the transfer and publication of manufacturer data. This was the case for the supplementary commission as well as for the first assessment. As the manufacturer also failed to provide a list of all studies conducted to date, it is unclear whether all relevant study results could be included in the assessment. It cannot therefore be excluded that the evidence base of the report is incomplete. During the course of the report production it also emerged that the company had already provided incorrect information following a request during the first benefit assessment: AstraZeneca concealed the fact that at the time of the first assessment, 2 additional studies had already been completed and analysed.

Procedure of report production

The preliminary results (preliminary report) were published by IQWiG at the beginning of June 2008 and interested parties were invited to submit comments to IQWiG. Unclear aspects from the comments on the preliminary report were discussed with the authors of the comments in an oral debate at the end of July 2008. The preliminary report was subsequently revised and the final report sent to the contracting agency, the Federal Joint Committee, in September 2008. The meeting minutes of the debate and the written comments will be published in a separate document at the same time as the final report.

The executive summary provides an overview of the background, methods, and further results of the final report.

Contact: Tel. ++49-0221-35685-0, info@iqwig.de