Are neuraminidase inhibitors effective for preventing and treating influenza in healthy adults and children?

Abstract

Background: Neuraminidase inhibitors are thought to help reduce the symptoms of influenza, with several possible mechanisms proposed. However, the evidence base for this class of agents remains a source of debate. In a previous review, we documented substantial risks of publication bias in trials of neuraminidase inhibitors for influenza (60 percent of patient data from phase III treatment trials of oseltamivir [Tamiflu] have never been published) and reporting bias in the published trials. Since that time, we have become aware of a large number of unpublished trials of neuraminidase inhibitors in the management of influenza; this review updates and merges existing reviews in this area. Objectives: To review clinical study reports of placebo-controlled randomized trials, regulatory comments, and reviews ("regulatory information") of the effects of the neuraminidase inhibitors, oseltamivir and zanamivir (Relenza), for influenza in all age groups, and to appraise trial programs, rather than single studies. Clinical study reports are very detailed, unpublished clinical trial data containing in-depth descriptions of protocol rationale, methods analysis plans, trial results, and organizational documents (such as contracts). Search Methods: We searched trial registries, cross-referencing published and unpublished sources, and corresponded with manufacturers and regulators. We searched the archives of the U.S. Food and Drug Administration and European and Japanese regulators. The evidence in this review reflects searches to obtain relevant information up to April 12, 2011. Selection Criteria: We included regulatory information based on assessments of randomized controlled trials conducted in persons of any age who had either confirmed or suspected influenza, or who had been exposed to influenza in the local community or their place of residence. Data Collection and Analysis: We indexed regulatory information in two purpose-built instruments and reconstructed trials using CONSORT statement-based templates. To progress to Stage 2 (full analysis), we sought manufacturer explanations of discrepancies in the data. GlaxoSmithKline offered us individual patient data and responded to our queries, but Roche did not provide us with complete clinical study reports. In Stage 2, we intended to analyze trials with validated data (i.e., assuming our validation questions aimed at clarifying omissions and discrepancies were resolved). No studies progressed to Stage 2. We carried out analyses of the effects of oseltamivir on time to first alleviation of symptoms and hospitalizations using the intention-to-treat population, and tested five hypotheses generated after protocol publication. Main Results: We included and analyzed data from 25 studies (15 oseltamivir and 10 zanamivir studies). The studies had adequate randomization and blinding procedures, but imbalances in the available analysis populations (intention-to-treat influenza-infected) left many of the studies at risk of attrition bias. All the studies were sponsored by manufacturers of neuraminidase inhibitors. Time to first alleviation of symptoms in persons with influenza-like illness symptoms (i.e., intention-to-treat population) was a median of 160 hours (range: 125 to 192 hours) in the placebo groups, and oseltamivir shortened this by around 21 hours (95% confidence interval [CI], -29.5 to -12.9 hours; P