Neuraminidase inhibitors for preventing and treating influenza in adults and children

  • Comment
  • Review
  • Intervention

Authors


Abstract

Background

Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide.

Objectives

To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments.

Search methods

We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database.

Selection criteria

Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza.

Data collection and analysis

We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers.

Main results

We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the zanamivir studies and half of the oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the oseltamivir studies and there was also evidence of selective reporting for both the zanamivir and oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances.

Time to first symptom alleviation. For the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P < 0.0001). This represents a reduction in the time to first alleviation of symptoms from 7 to 6.3 days. There was no effect in asthmatic children, but in otherwise healthy children there was (reduction by a mean difference of 29 hours, 95% CI 12 to 47 hours, P = 0.001). Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days, P < 0.00001), equating to a reduction in the mean duration of symptoms from 6.6 to 6.0 days. The effect in children was not significant. In subgroup analysis we found no evidence of a difference in treatment effect for zanamivir on time to first alleviation of symptoms in adults in the influenza-infected and non-influenza-infected subgroups (P = 0.53).

Hospitalisations. Treatment of adults with oseltamivir had no significant effect on hospitalisations: risk difference (RD) 0.15% (95% CI -0.78 to 0.91). There was also no significant effect in children or in prophylaxis. Zanamivir hospitalisation data were unreported.

Serious influenza complications or those leading to study withdrawal. In adult treatment trials, oseltamivir did not significantly reduce those complications classified as serious or those which led to study withdrawal (RD 0.07%, 95% CI -0.78 to 0.44), nor in child treatment trials; neither did zanamivir in the treatment of adults or in prophylaxis. There were insufficient events to compare this outcome for oseltamivir in prophylaxis or zanamivir in the treatment of children.

Pneumonia. Oseltamivir significantly reduced self reported, investigator-mediated, unverified pneumonia (RD 1.00%, 95% CI 0.22 to 1.49); number needed to treat to benefit (NNTB) = 100 (95% CI 67 to 451) in the treated population. The effect was not significant in the five trials that used a more detailed diagnostic form for pneumonia. There were no definitions of pneumonia (or other complications) in any trial. No oseltamivir treatment studies reported effects on radiologically confirmed pneumonia. There was no significant effect on unverified pneumonia in children. There was no significant effect of zanamivir on either self reported or radiologically confirmed pneumonia. In prophylaxis, zanamivir significantly reduced the risk of self reported, investigator-mediated, unverified pneumonia in adults (RD 0.32%, 95% CI 0.09 to 0.41); NNTB = 311 (95% CI 244 to 1086), but not oseltamivir.

Bronchitis, sinusitis and otitis media. Zanamivir significantly reduced the risk of bronchitis in adult treatment trials (RD 1.80%, 95% CI 0.65 to 2.80); NNTB = 56 (36 to 155), but not oseltamivir. Neither NI significantly reduced the risk of otitis media and sinusitis in both adults and children.

Harms of treatment. Oseltamivir in the treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90 to 7.39); number needed to treat to harm (NNTH) = 28 (95% CI 14 to 112) and vomiting (RD 4.56%, 95% CI 2.39 to 7.58); NNTH = 22 (14 to 42). The proportion of participants with four-fold increases in antibody titre was significantly lower in the treated group compared to the control group (RR 0.92, 95% CI 0.86 to 0.97, I2 statistic = 0%) (5% absolute difference between arms). Oseltamivir significantly decreased the risk of diarrhoea (RD 2.33%, 95% CI 0.14 to 3.81); NNTB = 43 (95% CI 27 to 709) and cardiac events (RD 0.68%, 95% CI 0.04 to 1.0); NNTB = 148 (101 to 2509) compared to placebo during the on-treatment period. There was a dose-response effect on psychiatric events in the two oseltamivir "pivotal" treatment trials, WV15670 and WV15671, at 150 mg (standard dose) and 300 mg daily (high dose) (P = 0.038). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75 to 10.29); NNTH = 19 (95% CI 10 to 57). There was a significantly lower proportion of children on oseltamivir with a four-fold increase in antibodies (RR 0.90, 95% CI 0.80 to 1.00, I2 = 0%).

Prophylaxis. In prophylaxis trials, oseltamivir and zanamivir reduced the risk of symptomatic influenza in individuals (oseltamivir: RD 3.05% (95% CI 1.83 to 3.88); NNTB = 33 (26 to 55); zanamivir: RD 1.98% (95% CI 0.98 to 2.54); NNTB = 51 (40 to 103)) and in households (oseltamivir: RD 13.6% (95% CI 9.52 to 15.47); NNTB = 7 (6 to 11); zanamivir: RD 14.84% (95% CI 12.18 to 16.55); NNTB = 7 (7 to 9)). There was no significant effect on asymptomatic influenza (oseltamivir: RR 1.14 (95% CI 0.39 to 3.33); zanamivir: RR 0.97 (95% CI 0.76 to 1.24)). Non-influenza, influenza-like illness could not be assessed due to data not being fully reported. In oseltamivir prophylaxis studies, psychiatric adverse events were increased in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07 to 2.76); NNTH = 94 (95% CI 36 to 1538) in the study treatment population. Oseltamivir increased the risk of headaches whilst on treatment (RD 3.15%, 95% CI 0.88 to 5.78); NNTH = 32 (95% CI 18 to 115), renal events whilst on treatment (RD 0.67%, 95% CI -2.93 to 0.01); NNTH = 150 (NNTH 35 to NNTB > 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116).

Authors' conclusions

Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence.

Resumo

Inibidores da neuraminidase para prevenir e tratar influenza em adultos e crianças saudáveis

Introdução

Os inibidores da neuraminidase são estocados e recomendados por agências de saúde pública para o tratamento e prevenção da influenza sazonal e pandêmica. Eles são utilizados clinicamente no mundo inteiro.

Objetivos

Descrever os benefícios e danos potenciais dos inibidores da neuraminidase para influenza em todas as faixas etárias através da revisão de todos os artigos de ensaios clínicos randomizados e placebo-controlados publicados e não publicados e de comentários regulatórios.

Métodos de busca

Fizemos buscas nas plataformas de registros de ensaios clínicos, em bases de dados eletrônicas (até 22 de julho de 2013) e arquivos regulatórios e nos correspondemos com fabricantes para identificar todos os estudos. Nós também solicitamos os relatórios de estudos clínicos. Nós focamos nas fontes de dados primárias dos fabricantes mas também verificamos se não havia ensaios clínicos randomizados (ECRs) de fontes que não tinham vínculo com os fabricantes através de buscas nas bases de dados eletrônicas: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (não MEDLINE), Database of Reviews of Effects, NHS Economic Evaluation Database e Health Economic Evaluations Database.

Critério de seleção

Incluímos ensaios clínicos randomizados ou placebo-controlados em adultos e crianças com exposição confirmada ou suspeita à influenza de ocorrência natural.

Coleta dos dados e análises

Nós extraímos dados e avaliamos o risco de viés dos usando instrumentos criados especificamente para esta revisão. Nós analisamos os efeitos do zanamivir e oseltamivir sobre os seguintes desfechos: tempo até o alívio dos sintomas, desfechos da influenza, complicações, internação e eventos adversos. As análises foram feitas segundo a intenção de tratar (ITT). Todos os estudos foram patrocinados pelos fabricantes dos medicamentos.

Principais resultados

Nós obtivemos 107 relatórios de ensaios clínicos da European Medicines Agency (EMA), Glaxo Smith Kline e Roche. Tivemos acesso aos comentários do US Food and Drug Administration (FDA), EMA e da agência regulatória do Japão. Nós incluímos 53 estudos em Fase 1 (avaliação da adequação do desenho do estudo) e 46 estudos em Fase 2 (análise formal), incluindo 20 estudos sobre oseltamivir (9.623 participantes) e 26 estudos sobre zanamivir (14.628 participantes). Devido a falhas na descrição dos estudos, a maioria dos estudos com zanamivir e metade dos estudos com oseltamivir foram classificadas como tendo alto risco de viés de seleção. Em 11 estudos com oseltamivir houve risco de viés de performance porque os placebos não tinham aparência idêntica. O viés de atrito (perda) foi alto nos estudos com oseltamivir e também houve evidência de viés de relato seletivo nos estudos com zanamivir e oseltamivir. As intervenções com placebo dos estudos com ambas as drogas podem ter contido substâncias ativas.

Tempo até o primeiro alívio de sintoma.O oseltamivir reduziu o tempo para o alívio de sintoma em 16.8 horas (intervalo de confiança de 95%, 95% CI, de 8,4 a 25,1 horas; P < 0,0001) nos adultos. Isso representa redução no tempo de alívio de sintoma de 7 para 6,3 dias. Não houve efeito nas crianças asmáticas. Nas crianças saudáveis, o oseltamivir reduziu esse tempo em média 29 horas, (95% CI de 12 a 47 horas, P = 0,001). Nos adultos, o zanamivir reduziu o tempo para o alívio de sintoma em 0,60 dias (95% CI 0,39 a 0,81 dias; P < 0,00001), equivalendo a uma redução na duração média dos sintomas de 6,6 para 6,0 dias. O efeito em crianças não foi significante. Não houve diferença no tempo para o alívio dos sintomas na análise dos subgrupos de adultos infectados e não infectatos por influenza que usaram zanamivir (P = 0,53).

Hospitalizações.Nos adultos, o uso do oseltamivir não modificou significativamente o risco de internação hospitalar: diferença de risco (DR) 0,15% (95% CI de -0,78 a 0,91). Não houve efeito significativo em crianças ou quanto o medicamento foi usado profilaticamente. Os efeitos do zanamivir sobre o risco de internação não foram relatados.

Complicações graves da influenza ou complicações que levaram ao abandono do estudo.Em estudos com adultos, o oseltamivir não reduziu significantemente as complicações classificadas como graves ou aquelas que levaram ao abandono do estudo (DR 0,07%, 95% CI -0,78 a 0,44), nem em estudos com crianças. O mesmo ocorreu com o zanamivir usado para o tratamento ou a profilaxia de adultos. Não houve eventos suficientes para comparar esse desfecho com uso profilático de oseltamivir ou com zanamivir para o tratamento em crianças.

Pneumonia.O oseltamivir reduziu significantemente a pneumonia auto-relatada, relatada pelo investigador e não comprovada (DR 1,00%, 95% CI 0,22 a 1,49); com número necessário para tratar para beneficiar (NNTB) = 100 (95% CI 67 a 451) na população tratada. Nos cinco estudos que utilizaram uma forma de diagnóstico mais detalhada para pneumonia, o efeito não foi significativo. Nenhum dos estudos definiu pneumonia (ou outras complicações). Nenhum dos estudos com oseltamivir relatou efeitos em pneumonia que fossem confirmados radiologicamente. Não houve efeito significante em pneumonia não comprovada em crianças. Não houve efeito significante de zanamivir sobre pneumonia auto-relatada ou confirmada radiologicamente. O uso profiláticos do zanamivir reduziu significantemente o risco de pneumonia auto-relatada, informada pelo investigador ou não verificada em adultos (DR 0,32%, 95% CI 0,09 a 0,41); NNTB = 311 (95% CI 244 a 1.086), mas não o oseltamivir.

Bronquite, sinusite e otite média.O zanamivir reduziu significantemente o risco de bronquite nos estudos que trataram adultos (DR 1,80%, 95% CI 0,65 a 2,80); NNTB = 56 (36 a 155), mas o oseltamivir não teve esse efeito. Nenhum inibidores da neuraminidase reduziu significantemente o risco de otite média e sinusite em adultos ou crianças.

Danos do tratamento.O oseltamivir para o tratamento em adultos aumentou o risco de náusea (DR 3,66%, 95% CI 0,90 a 7,39); o número necessário para tratar para danos (NNTH) = 28 (95% CI 14 a 112) e vômitos (DR 5,56%, 95% CI 2,39 a 7,58); NNTH = 22 (14 a 42). A proporção de participantes que aumentou em quatro vezes o título de anticorpos foi significantemente menor para o grupo tratado comparado com o grupo controle (RR 0,92, 95% CI 0,86 a 0,97, I2 = 0%; diferença absoluta de 5% entre os braços). O oseltamivir diminuiu significantemente o risco de diarreia (DR 2,33%, 95% CI 0,14 a 3,81); NNTB = 43 (95% CI 27 a 709) e eventos cardíacos (DR 0,68%, 95% CI 0,04 a 1,0); NNTB = 148 (101 a 2509) comparado com placebo, durante o período de tratamento. Houve um efeito de dose-resposta para eventos psiquiátricos nos dois estudos principais de tratamento com o oseltamivir, WV15670 e WV 15671, com 150 mg (dose padrão) e 300 mg (dose alta) ao dia (P = 0,038). O tratamento de crianças com oseltamivir induziu o vômito (DR 5,34%, 95% CI 1,75 a 10,29; NNTH = 19; 95% CI 10 a 57). Uma proporção significativamente menor de crianças usando oseltamivir teve aumento de quatro vezes nos títulos de anticorpos (RR 0,90, 95% CI 0,80 a 1,00, I2 = 0%).

Profilaxia.Nos estudos de profilaxia, o oseltamivir e o zanamivir reduziram o risco de influenza sintomática em indivíduos [oseltamivir: DR 3,05% (95% CI 1.83 a 3.88); NNTB = 33 (26 a 55); zanamivir: RD 1,98% (95% CI 0,98 a 2,54); NNTB = 51 (40 a 103)] e em famílias (oseltamivir: DR 13,6; 95% CI 9,52 a 15,47; NNTB = 7; 6 a 11; zanamivir: DR 14,84%; 95% CI 12,18 a 16,55; NNTB = 7; 7 a 9). Não houve efeito significante sobre influenza assintomática (oseltamivir: RR 1.14; 95% CI 0,39 a 3,33; zanamivir: RR 0,97; 95% CI 0,76 a 1.24). Devido à falta de informações completas, não foi possível avaliar as doenças não influenza e parecidas com influenza ("influenza-like"). Nos estudos profiláticos com oseltamivir, houve aumento nos eventos adversos psiquiátricos durante o tempo que incluía os períodos de tratamento e não tratamento (DR 1,06%, 95% CI 0,07 a 2,76; NNTH = 94; 95% CI 36 a 1.538) na população em tratamento. O oseltamivir aumentou o risco de cefaleia durante o seu uso (DR 3,15%, 95% CI 0,88 a 5,78; NNTH = 32; 95% CI 18 a 115), de eventos renais durante o uso (DR 0,67%, 95% CI -2,93 a 0,01; NNTH = 150; NNTH 35 a NNTB > 1000) e náusea durante o uso (DR 4,15%, 95% CI 0,86 a 9,51; NNTH = 25; 95% CI 11 a 116).

Conclusão dos autores

O oseltamivir e o zanamivir têm efeitos pequenos e não específicos na redução do tempo para alívio dos sintomas da influenza em adultos, mas não houve efeito em crianças asmáticas. O uso profilático de qualquer dessas drogas diminui o risco de desenvolver influenza sintomática. Devido à falta de definições diagnósticas, os estudos de tratamento com oseltamivir ou zanamivir não responderam à questão se esses medicamentos reduzem as complicações da influenza (como a pneumonia). O uso de oseltamivir aumenta o risco de eventos adversos como náuseas, vômitos, efeitos psiquiátricos e eventos renais em adultos e o risco de vômito em crianças. A baixa biodisponibilidade do zanamivir pode explicar a baixa toxicidade desse medicamento em comparação com o oseltamivir. O equilíbrio entre os benefícios e danos deve ser considerado na tomada de decisão do uso dos dois inibidores da neuraminidase tanto para profilaxia quanto para o tratamento da influenza. O mecanismo de ação específico desses medicamentos sobre o vírus da influenza proposto pelos fabricantes não se enquadra nas evidências clínicas.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Maíra Tristão Parra).

摘要

預防與治療成人及兒童流感之神經胺酸酶抑制劑

背景

神經胺酸酶抑制劑(NIs),為公共衛生單位對於治療與預防季節性及傳染性流感之儲備與建議用藥,它們在世界各地臨床上皆被使用。

目的

為了描述NIs對於流感在各年齡族群中潛在的效益與危害,回顧所有包含已發表與未發表的隨機安慰劑對照試驗與法規評論的臨床研究報告。

搜尋策略

我們搜尋了試驗記錄、電子資料庫(直至2013年7月22日)與法規檔案庫並與製造商連繫,以確認所有的試驗,也要求提供臨床研究報告。我們著重於製造商的原始資料,在下列資料庫做了電子搜尋後,發現在已發表的隨機對照試驗(RCTs)中,沒有來自非製造商的:Cochrane Central Register of Controlled Trials (CENTRAL)、MEDLINE、MEDLINE (Ovid)、EMBASE、Embase.com、PubMed (非MEDLINE)、Database of Reviews of Effects、NHS Economic Evaluation Database以及Health Economic Evaluations Database等資料庫。

選擇標準

對於已確診或疑似暴露在自然產生的流感中之成人及兒童的隨機安慰劑對照試驗。

資料收集與分析

我們摘錄臨床研究報告,並以特殊目地為導向的工具來評估偏誤風險。我們分析了zanamivir與oseltamivir在到初次症狀緩解所需時間、流感結果、併發症、住院治療與不良事件上,對於治療意向人數的效應。所有的試驗皆由製造商贊助。

主要結果

我們由歐洲藥物管理局(EMA)、GlaxoSmithKline及Roche公司取得107份臨床研究報告,且獲取美國食品藥物管理局(FDA)、EMA以及日本管理機關所做的評論。收錄了53個在第一階段的試驗(合適的研究設計之判斷)以及46個在第二階段的試驗(正式分析),包含20個oseltamivir(9,623位受試者)與26個zanamivir(14,628位受試者)的試驗。不合適的報告讓大部分的zanamivir研究與一半的oseltamivir研究有高選擇偏誤風險。為避免11個oseltamivir研究出現因安慰劑呈現方式不同而產生的表現性偏誤,因此執行了一些不合適的措施。損耗性偏差在oseltamivir研究中為高,且zanamivir及oseltamivir研究皆有選擇性報告的證據。安慰劑干預在兩階段的試驗中皆可能含有活性物質。

到初次症狀緩解所需時間。對於成人的治療,oseltamivir將到初次症狀緩解所需時間減少了16.8小時(95% 信賴區間(CI) 8.4至25.1小時, P < 0.0001),這代表到初次症狀緩解所需時間由7天減少至6.3天。對於有氣喘的兒童沒有影響,相反的,對健康的兒童則有(減少了29小時的平均差, 95% CI 12至47小時, P = 0.001)。Zanamivir在成人上將到初次症狀緩解所需時間減少了0.60天(95% CI 0.39至0.81天, P < 0.00001),等於將症狀的平均持續期由6.6天減少至6.0天,對於兒童的影響則不顯著。在次群組分析中我們發現,zanamivir在次群組中對於已受流感感染及未受流感感染(P = 0.53)的成人,到初次症狀緩解所需時間的治療效果沒有證據顯示差異。

住院治療。Oseltamivir治療對成人住院治療沒有顯著的影響:風險差(RD) 0.15% (95% CI -0.78至0.91),對於兒童或預防也沒有顯著的影響。沒有zanamivir的住院治療資料記錄。

嚴重或導致研究中止的流感併發症。成人治療試驗中,oseltamivir並無顯著減少那些被歸類為嚴重或是導致研究中止的併發症(RD 0.07%, 95% CI -0.78至0.44),在兒童治療試驗中也沒有影響;而zanamivir對成人治療或預防也皆無影響。沒有足夠的事件能將此結果與oseltamivir對於預防或zanamivir對於兒童治療做比較。

肺炎。Oseltamivir顯著地減少了自覺性、經檢查發現以及未確診的肺炎(RD 1.00%, 95% CI 0.22至1.49);被治療的人口中,益一需治數(NNTB)為100。在5個使用更詳盡的形式來診斷肺炎的試驗中,效應並不顯著。任一試驗中皆無對於肺炎(或其他併發症)的定義。Oseltamivir的治療研究沒有記錄對於經放射確診的肺炎之影響,對於兒童未確診肺炎則沒有顯著影響。Zanamivir對自覺性或經放射確診的肺炎皆無顯著的影響。在預防上,zanamivir顯著地降低成人罹患自覺性、經檢查發現或未確診的肺炎風險(RD 0.32%, 95% CI 0.09至0.41);NNTB=311(95% CI 244至1086),但oseltamivir則無。

支氣管炎、鼻竇炎及中耳炎。Zanamivir在成人治療試驗中,顯著地降低罹患支氣管炎的風險(RD 1.80%, 95% CI 0.65至2.80);NNTB = 56 (36 to 155),但oseltamivir則無。NI在成人及兒童中,皆無顯著降低罹患中耳炎與鼻竇炎的風險。

治療的危害。Oseltamivir在成人治療中,增加噁心(RD 3.66%, 95% CI 0.90至7.39);害一需治數(NNTH)為28 (95% CI 14至112)與嘔吐(RD 4.56%, 95% CI 2.39至7.58);NNTH = 22 (14至42)的風險。實驗組中,抗體力價增加四倍的受試者比例明顯低於對照組(RR 0.92, 95% CI 0.86至0.97, I2 statistic = 0%) (5% 雙臂間的絕對差量)。在治療期間,oseltamivir較安慰劑顯著地降低了腹瀉(RD 2.33%, 95% CI 0.14至3.81); NNTB = 43 (95% CI 27至709)及心臟相關疾病(RD 0.68%, 95% CI 0.04至1.0);NNTB = 148 (101至2509)的風險。在2個oseltamivir核心治療試驗WV15670及WV15671中,每日150 mg (標準劑量)與300 mg (高劑量) (P = 0.038),在精神病症狀上有劑量效應。在兒童治療中,oseltamivir導致嘔吐(RD 5.34%, 95% CI 1.75至10.29);NNTH = 19 (95% CI 10至57);使用oseltamivir的兒童中,抗體增加四倍的比例顯著較少(RR 0.90, 95% CI 0.80至1.00, I2 = 0%)。

預防。在預防試驗中,oseltamivir與zanamivir降低了個人症狀性流感(oseltamivir:RD 3.05% (95% CI 1.83至3.88);NNTB = 33 (26至55);zanamivir:RD 1.98% (95% CI 0.98至2.54);NNTB = 51 (40至103))與居家流感(oseltamivir:RD 13.6% (95% CI 9.52至15.47);NNTB = 7 (6至11);zanamivir:RD 14.84% (95% CI 12.18至16.55);NNTB = 7 (7至9))的風險。在無症狀流感上則無顯著的影響(oseltamivir:RR 1.14 (95% CI 0.39至3.33); zanamivir:RR 0.97 (95% CI 0.76至1.24))。由於資料沒有完全地記錄下來,無法評估非流感、類流感疾病。在oseltamivir預防研究中,研究治療群體的精神不良事件在治療與非治療期中皆增加(RD 1.06%, 95% CI 0.07至2.76); NNTH = 94 (95% CI 36至1538)。Oseltamivir在治療期中增加了頭痛(RD 3.15%, 95% CI 0.88至5.78);NNTH = 32 (95% CI 18至115)、腎臟相關事件(RD 0.67%, 95% CI -2.93至0.01);NNTH = 150 (NNTH 35至NNTB > 1000)以及噁心(RD 4.15%, 95% CI 0.86至9.51);NNTH = 25 (95% CI 11至116)的風險。

作者結論

Oseltamivir與zanamivir在縮短成人流感症狀緩解所需時間上有小而不特定的影響,但在氣喘兒童上則無。使用任一種藥品做為預防,可以減低罹患症狀性流感的風險。由於缺乏診斷定義,包含oseltamivir或zanamivir的治療試驗無法解決流感併發症(例如肺炎)是否減少的問題。Oseltamivir的使用,增加成人出現不良效應,例如噁心、嘔吐、精神影響及腎臟相關事件與兒童出現嘔吐的風險。較低的生體可用率也許可以解釋zanamivir的毒性為何較oseltamivir低。在做關於是否使用兩種NIs來預防或治療流感的決定時,需考量效益與危害之間的平衡。製造商提出的流感病毒特異作用機轉與臨床證據不符。

譯註

翻譯者:臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

摘要

神经氨酸酶抑制剂用于预防和治疗成人和儿童流感

研究背景

神经氨酸酶抑制剂被公共卫生机构储备并推荐用于治疗和预防季节性和大流行性流感。它们在全世界各地的临床上皆被使用。

研究目的

通过综述已发表和未发表的随机、安慰剂对照试验和监管评论的所有临床研究报告,描述NIs对所有年龄组流感患者的潜在疗效和危害。

检索策略

我们检索了试验注册库,电子数据库(到2013年7月22日)和监管档案,并与制造商联系,以确认所有试验。我们还要求提供临床研究报告。我们主要关注制造商来源的原始数据,但是我们也通过在以下数据库中进行电子检索,核查到没有非制造商来源的的随机对照试验发表:Cochrane对照试验中心注册库(CENTRAL),MEDLINE,MEDLINE(Ovid),EMBASE,Embase.com,PubMed(非MEDLINE),疗效综述数据库(Database of Reviews of Effects),NHS经济评估数据库和卫生经济评估数据库。

标准/纳入排除标准

对于已确诊或疑似暴露在自然产生的流感中的成年人和儿童的随机、安慰剂对照试验。

数据收集与分析

我们提取了临床研究报告数据,并使用特制工具评估偏倚风险。采用意向性分析的方法对扎那米韦和奥司他韦治疗的首次症状缓解时间,流行性感冒结局,并发症,住院和不良事件的疗效进行分析。所有试验由制造商赞助。

主要结果

我们获得了欧洲药品管理局(European Medicines Agency, EMA),葛兰素史克公司和罗氏公司的107份临床研究报告,且获取了美国食品和药物管理局(Food and Drug Administration, FDA),EMA和日本监管机构所做的评论。我们在第1阶段(适当的研究设计的判断)纳入53项试验,在第2阶段(正式分析)纳入46项试验,其中包括20项奥司他韦试验(9623名参与者)和26项扎那米韦试验(14,628名参与者)。报告不足使得大多数扎那米韦研究和一半的奥司他韦研究有高风险的选择偏倚。由于安慰剂的表现形式不相同,且没有采取足够的措施,11项奥司他韦研究会出现实施偏倚风险。奥司他韦研究中的磨损偏倚很高,并且有证据表明扎那米韦和奥司他韦研究出现了选择性报告的情况。两种药物试验中的安慰剂干预可能含有活性物质。

首次症状缓解时间。在治疗成年人时,奥司他韦可以将首次症状缓解时间减少16.8小时(95%置信区间(Confidence Interval, CI)8.4 - 25.1小时,P<0.0001)。这表示首次症状缓解时间从7天减少到6.3天。治疗哮喘儿童无效,但健康儿童有效(减少的平均差异为29小时,95%CI 12- 47小时,P=0.001)。扎那米韦可以将成年人首次症状缓解时间减少0.6天(95%CI 0.39 - 0.81天,P<0.00001),相当于将平均症状时间从6.6天减少到6天。但对儿童的疗效并不显著。在亚组分析中,我们发现没有证据表明,在流感感染和非流感感染亚组中,扎那米韦对成人首次症状缓解的治疗效果有差异(P=0.53)。

住院治疗。 奥司他韦治疗对成人住院治疗无明显影响:风险差(Risk Difference, RD)为0.15%(95%CI -0.78 - 0.91)。对于儿童或预防也没有显著效果。没有扎那米韦住院治疗的数据记录。

严重的流感并发症或导致试验退出的并发症。在成人治疗试验中,奥司他韦并没有显著降低那些被归类为严重或导致研究退出的并发症(RD 0.07%,95%CI -0.78 - 0.44),儿童治疗试验中也如此。扎那米韦治疗成人或用于预防也没有显著降低。没有足够的事件数来统计当奥司他韦用于预防或扎那米韦用于治疗儿童时这一结局的组间差异。

肺炎。奥司他韦显著地降低了自报告、经检查发现以及未确诊的肺炎的发生(RD 1.00%,95%CI 0.22 - 1.49);待治疗人群中,益一需治疗数(Number Needed to be Treated, NNTB)为 100(95%CI 67 - 451)。在采用了更详细的肺炎诊断方式的五项试验中,这一效果并不显著。所有试验中都没有对肺炎(或其他并发症)的定义。没有一项奥司他韦治疗研究报告了对于经放射确诊的肺炎的影响。对儿童未经证实的肺炎则无显著影响。扎那米韦对自我报告的或放射学证实的肺炎无显著影响。在预防上,扎那米韦可以显著降低成人罹患自报告的,经证实的和未经证实的肺炎的风险(RD 0.32%,95%CI 0.09 - 0.41);NNTB 311(95%CI 244 - 1086),但奥司他韦则不能。

支气管炎,鼻窦炎和中耳炎。扎那米韦能显著降低成人罹患支气管炎的风险(RD 1.80%,95%CI 0.65 - 2.80);NNTB 56(36 - 155),但奥司他韦则不能。不论是对于成人还是儿童,NI都不能显著降低其患中耳炎和鼻窦炎的风险。

治疗伤害。 奥司他韦在成人治疗中会增加恶心的风险(RD 3.66%,95%CI 0.90 - 7.39),害一需治疗数(Number Needed to Treat to Harm, NNTH)28(95%CI 14 - 112);也会增加呕吐发生的风险(RD 4.56%,95%CI 2.39 - 7.58);NNTH 22(14 - 42)。与对照组相比,治疗组抗体滴度增加4倍的受试者比例显著降低(RR 0.92,95%CI 0.86 - 0.97,I2统计值 = 0%)(组间绝对差异5%)。在治疗期间,与安慰剂相比,奥司他韦能显着降低腹泻风险(RD 2.33%,95%CI 0.14 - 3.81),NNTB 43(95%CI 27 - 709),和心脏不良事件数(RD 0.68%,95%CI 0.04 - 1.0),NNTB 148(101 - 2509)。在两项奥司他韦“关键”治疗试验(WV15670和WV15671)中,每日150mg(标准剂量)和300mg(高剂量)(P=0.038)在精神病学事件发生发面存在剂量效应关系。在儿童治疗中,奥司他韦会诱发呕吐发生(RD 5.34%,95%CI 1.75 - 10.29);NNTH 19(95%CI 10 - 57)。奥司他韦组抗体增加4倍的儿童比例显着降低(RR 0.90,95%CI 0.80 - 1.00,I2 = 0%)。

预防。 在预防试验中,奥司他韦和扎那米韦降低了个体发生症状性流感的风险(奥司他韦:RD 3.05%(95%CI 1.83 - 3.88);NNTB 33(26 - 55);扎那米韦:RD 1.98%(95%CI 0.98 - 2.54);NNTB 51(40 - 103))和家庭发生症状性流感的风险(奥司他韦:RD 13.6%(95%CI 9.52 - 15.47);NNTB 7(6 - 11);扎那米韦:RD为14.84%(95%CI 12.18 - 16.55);NNTB 7(7 - 9))。对无症状流感无显著影响(奥司他韦:RR 1.14(95%CI 0.39 - 3.33));扎那米韦:RR 0.97(95%CI 0.76 - 1.24))。非流感、流感样疾病由于数据未得到充分报告而无法评估。在奥司他韦预防研究中,精神不良事件在治疗和非治疗期中均增加(RD 1.06%,95%CI 0.07 - 2.76);研究治疗人群中NNTH 94(95%CI 36 - 1538)。奥司他韦在治疗时会增加头痛(RD 3.15%,95%CI 0.88 - 5.78);NNTH= 32(95%CI 18 - 115),肾脏事件(RD 0.67%,95%CI -2.93 - 0.01);NNTH 150(NNTH 35 - NNTB> 1000),恶心(RD 4.15%,95%CI 0.8 - 9.51);NNTH 25(95%CI 11 - 116)的发生风险。

作者结论

奥司他韦和扎那米韦对减少成年人流感症状缓时间有很小的非特异性疗效,但对哮喘儿童则没有。使用这两种药物作为预防措施可降低发生症状性流感的风险。由于缺乏诊断定义,奥司他韦或扎那米韦的治疗试验不能解决流感并发症(如肺炎)是否减少的问题。奥司他韦的使用增加了不良效应的风险,如成人的恶心,呕吐,精神影响和肾脏事件以及儿童呕吐。较低的生物利用度可以解释与奥司他韦相比,扎那米韦的毒性较低。在作出有关使用NI预防或治疗流感的决定时,应考虑获益与危害之间的平衡。制造商提出的流感病毒特异性作用机制不符合临床证据。

翻译注解

译者:李文元,审校:梁宁。北京中医药大学循证医学中心2017年6月28日

Plain language summary

Regulatory information on trials of oseltamivir (Tamiflu) and zanamivir (Relenza) for influenza in adults and children

Oseltamivir and zanamivir have been stockpiled in many countries to treat and prevent seasonal and pandemic influenza, before an influenza vaccine matched to the circulating virus becomes available. Oseltamivir is classified by the World Health Organization as an essential medicine.

How this review has been approached

We have updated and combined our reviews on the antiviral drugs zanamivir and oseltamivir for influenza in adults and children on the basis of the manufacturers' reports to regulators (clinical study reports) and the regulators' comments. We have called these comments and reports 'regulatory information'. Clinical study reports are unpublished, extensive documents with great detail on the trials that formed the basis for market approval. They include the protocols, methods and results. Clinical study reports have until now been confidential, seen only by the manufacturers and regulators.

Why we have taken this approach

In previous versions of this review we identified unresolved discrepancies in the data presented in published trial reports and substantial publication bias. As a consequence, we elected not to use data from journal articles but included the documents generated during licensing processes. We have accessed such data from the UK, USA, European Medicines Agency (EMA), Japanese regulators and clinical study reports from the manufacturers (after a protracted media campaign). This has enabled us to verify information from the randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza.

Based on our assessments of the regulatory documents (in excess of 160,000 pages), we came to the conclusion that there were substantial problems with the design, conduct, reporting and availability of information from many of the trials.

What we have found

We have used data from 46 trials (20 oseltamivir and 26 zanamivir studies) in this review. We identified problems in the design of many of the studies that we included, which affects our confidence in their results. We found that both drugs shorten the duration of symptoms of influenza-like illness (unconfirmed influenza or 'the flu') by less than a day. Oseltamivir did not affect the number of hospitalisations, based on the data from all the people enrolled in treatment trials of oseltamivir. Zanamivir trials did not record this outcome. The effects on pneumonia and other complications of influenza, such as bronchitis, middle ear infection (otitis media) and sinusitis, were unreliably reported, as shown by the case report form in the trial documents. Some forms showed limitations in the diagnostic criteria for pneumonia. Regulatory comments noted problems with missing follow-up diary cards from participants. In children with asthma there was no clear effect on the time to first alleviation of symptoms.

Prophylaxis trials showed that oseltamivir and zanamivir reduced the risk of symptomatic influenza in individuals and households. There was no evidence of an effect on asymptomatic influenza or on non-influenza, influenza-like illness, but trial conduct problems prevent any definitive conclusion.

Oseltamivir use was associated with nausea, vomiting, headaches, renal and psychiatric events; these last three were when it was used to prevent influenza (prophylaxis). Its effect on the heart is unclear: it may reduce cardiac symptoms, but may induce serious heart rhythm problems. In adult treatment trials of zanamivir there was no increased risk of reported adverse events. The evidence on the possible harms associated with the treatment of children with zanamivir was sparse.

Agreement with other findings

The lack of good evidence demonstrating an effect on complications agrees with the conservative conclusions on both drugs drawn by the US Food and Drug Administration (FDA). The FDA only allowed claims of effectiveness of both drugs for the prevention and treatment of symptoms of influenza and not for other effects (including the interruption of person-to-person spread of the influenza virus or prevention of pneumonia). The FDA described the overall performance of both drugs as 'modest'.

Mechanism of action for beneficial effects

These findings all suggest that the low immune response with low levels of pro-inflammatory cytokines, which is induced by the action of oseltamivir carboxylate, may reduce the symptoms of influenza unrelated to an inhibition of influenza virus replication. The potential hypothermic or antipyretic effect of oseltamivir as a central nervous system depressant may also contribute to the apparent reduction of host symptoms. Statements made on the capacity of oseltamivir to interrupt viral transmission and reduce complications are not supported by any data we have been able to access.

The mechanism of action proposed by the producers (influenza virus-specific) does not fit the clinical evidence which suggests a multi-system and central action.

Laienverständliche Zusammenfassung

Ergebnisse aus Zulassungsstudien mit Oseltamivir (Tamiflu) und Zanamivir (Relenza) für Grippe bei Erwachsenen und Kindern

Oseltamivir und Zanamivir wurden in vielen Ländern bevorratet, um eine saisonale oder pandemische Grippe zu behandeln bzw. ihr vorzubeugen, bevor eine Grippeimpfung verfügbar ist, die an den aktuell zirkulierenden Virustyp angepasst ist. Oseltamivir wird von der Welt- gesundheitsorganisation als notwendiges Medikament eingestuft.

Wie dieser Review durchgeführt wurde

Wir haben unsere Reviews zu den antiviralen Medikamenten Zanamivir und Oseltamivir bei Erwachsenen und Kindern auf den neuesten Stand gebracht und zusammengeführt. Dabei haben wir uns auf die Berichte der Hersteller an die Zulassungsbehörden (klinische Studien- berichte) und die Kommentare dieser Behörden gestützt. Diese Berichte und Kommentare werden im Weiteren als ‘Zulassungsdokumente’ bezeichnet. Klinische Studienberichte sind unveröffentlichte Dokumente, die umfangreiche Daten über Studien enthalten, welche die Grundlage für die Marktzulassung eines Medikamentes sind. Sie enthalten Studienprotokolle, sowie Beschreibungen der Methoden und Ergebnisse. Diese klinischen Studienberichte waren bisher vertraulich und nur den Herstellern und Zulassungsbehörden zugänglich.

Warum diese Vorgehensweise gewählt wurde

In vorherigen Versionen dieses Reviews hatten wir Unstimmigkeiten in den Daten der publizierten Studienberichte, die nicht geklärt werden konnten, sowie einen erheblichen Publikationsbias gefunden. Daher entschieden wir uns, statt der Daten aus den wissen- schaftlichen Artikeln die Dokumente aus den Zulassungsverfahren zu verwenden. Wir hatten Zugang zu Daten der Zulassungsbehörden in Grossbritannien, USA und Japan und der European Medicines Agency (EMA) und zu klinischen Studienberichten der Hersteller (nach einer langwierigen Medienkampagne). Dadurch waren wir in der Lage, die Informationen derjenigen randomisierten, plazebo-kontrollierten Studien zu überprüfen, an denen Erwachsene und Kinder mit bestätigter oder vermuteter Exposition gegenüber natürlich vorkommender Grippe teilgenommen hatten.

Wir kamen aufgrund unserer Auswertung der Zulassungsdokumente (mehr als 160000 Seiten) zum Schluss, dass für viele Studien sowohl das Studiendesign, die Durchführung, die Berichtsqualität als auch die Verfügbarkeit der Daten problematisch waren.

Was wir gefunden haben

In diesem Review wurden die Daten von 46 Studien (20 zu Oseltamivir und 26 zu Zanamivir) berücksichtigt. Im Design vieler eingeschlossener Studien fanden wir Schwachpunkte, weshalb die Ergebnisse nur bedingt vertrauenswürdig sind. Beide Wirkstoffe verkürzen die Dauer von Symptomen einer grippeähnlichen Erkrankung (unbestätigte Influenza-Erkrankung oder sogenannte «Grippe») um weniger als einen Tag. Basierend auf den Daten aller mit Oseltamivir durchgeführten Studien hatte der Wirkstoff keine Auswirkung auf die Zahl der Krankenhausaufnahmen. Für Zanamivir wurde dieser Studienendpunkt nicht erhoben. Die Wirksamkeit bezüglich Lungenentzündung und anderer Grippekomplikationen (wie z.B. Bronchitis, Mittelohrentzündung, Nasennebenhöhlenentzündung) wurde nicht verlässlich erfasst, wie aus den in den Zulassungsdokumenten enthalten Erhebungsbögen ersichtlich ist. In einigen dieser Erhebungsbögen waren die Kriterien für die Diagnose einer Lungenentzündung unzureichend bestimmt. In den Kommentaren der Zulassungsbehörden wurden Probleme mit fehlenden Akteneinträgen während der Nachbeobachtung der Teilnehmer verzeichnet. Bei Kindern mit Asthma gab es keine eindeutige Wirkung bezüglich der Zeit bis zur Besserung der Symptome.

In Studien zur Grippevorbeugung verminderten Oseltamivir und Zanamivir das Risiko einer symptomatischen Grippe sowohl bei Einzelpersonen als auch in Haushalten. Eine Wirksamkeit bezüglich Grippeinfektion ohne Symptome oder grippeähnlicher Erkrankungen ohne Influenza- Infektion konnte nicht nachgewiesen werden. Allerdings können aufgrund der Probleme bei der Durchführung der Studien keine definitiven Schlüsse gezogen werden.

Die Einnahme von Oseltamivir ging sowohl mit Übelkeit und Erbrechen einher als auch mit Kopfschmerzen, Nierenproblemen und psychiatrischen Symptomen. Die letztgenannten drei Nebenwirkungen traten auf, wenn Oseltamivir zur Vorbeugung (Prophylaxe) eingesetzt wurde. Seine Wirkung auf das Herz ist unklar: es vermindert möglicherweise kardiale Symptome, kann aber vermutlich schwere Herzrhythmusstörungen hervorrufen. In Zanamivir-Therapiestudien bei Erwachsenen bestand kein erhöhtes Risiko für (berichtete) Nebenwirkungen. Zu möglichen Nebenwirkungen bei der Behandlung von Kindern mit Zanamivir war die Datenlage dürftig.

Übereinstimmung mit anderen Ergebnissen

Das Fehlen von guter Evidenz dafür, dass beide Wirkstoffe Grippekomplikationen vermindern, stimmt mit den zurückhaltenden Schlussfolgerungen der US Food and Drug Administration (FDA) überein. Die FDA liess lediglich zu, dass die Wirksamkeit beider Medikamente für die Vorbeugung und Behandlung von Grippesymptomen genannt werden darf, nicht jedoch für andere Aspekte (wie die Unterbrechung der Weiterverbreitung des Grippevirus zwischen Personen und die Vorbeugung von Lungenentzündungen). Die FDA beschrieb die allgemeine Wirkung beider Medikamente als ‘mässig’.

Mechanismus der beabsichtigten Wirkung

Alle Ergebnisse legen nahe, dass die reduzierte Immunantwort mit niedrigen Spiegeln von entzündungsfördernden Zytokinen, die durch Oseltamivircarboxylat ausgelöst wird, die Grippesymptomatik vermindert, und dies unabhängig von einer Hemmung der Vermehrung des Grippevirus ist. Eine mögliche hypotherme oder fiebersenkende Wirkung von Oseltamivir als einem Stoff, der das zentrale Nervensystem dämpft, trägt möglicherweise ebenso zur Reduktion der Symptomatik bei. Die Daten, die uns zur Verfügung standen, bestätigen jedoch nicht die Aussage, dass Oseltamivir die Übertragung des Virus unterbricht und Komplikationen vermindert.

Der von den Herstellern angeführte (Influenzavirus-spezifische) Wirkmechanismus passt nicht zur klinischen Evidenz, die eine zentrale Wirkung in mehreren Organsystemen nahelegt.

Anmerkungen zur Übersetzung

Cochrane Schweiz

Laički sažetak

Priopćenja regulatornih tijela o kliničkim ispitivanjima oseltamivira (Tamiflu) i zanamivira (Relenza) u prevenciji i liječenju gripe (influenca) odraslih i djece

Lijekovi oseltamivir i zanamivir nabavljeni su u mnogim državama za liječenje i prevenciju sezonske i pandemične gripe prije nego što cjepivo protiv gripe koje se poklapa s cirkulirajućim sojem virusa gripe postane dostupno. Oseltamivir se nalazi na listi neophodnih lijekova Svjetske zdravstvene organizacije.

Kako se pristupilo izradi ovoga sustavnog pregleda?

Obnovljeni su i objedinjeni Cochrane sustavni pregledi o antivirusnim lijekovima zanamiviru i oseltamiviru kao terapija u odraslih i djece za gripu temeljem izviješća proizvođača navedenih lijekova regulatornim tijelima (izvješća o kliničkim ispitivanjima koja se predaju regulatornim tijelima u svrhu odobrenja lijeka na tržištu) i tumačenja regulatornih tijela. Navedena tumačenja i izvješća nazvana su priopćenja regulatornih tijela. Izvješća kliničkih ispitivanja se javno ne objavljuju i najopsežniji su dokumenti koji sadrže detaljne podatke iz kliničkih ispitivanja, a čine temeljnu dokumentaciju koju je potrebno dostaviti regulatornim tijelima za odobrenje stavljanja lijekova na tržište. Uključuju plan kliničkog ispitivanja, metode i rezultate. Izvješća kliničkih ispitivanja dugo su bila povjerljiva, dostupna samo proizvođačima lijekova i regulatornim tijelima.

Zašto je upotrijebljen takav pristup ovom istraživanju?

U prethodnim inačicama sustavnog pregleda uočena je neusklađenost podataka u objavljenim kliničkim ispitivanjima i značajna pristranost prilikom objavljivanja kliničkih ispitivanja. Zbog toga su autori sustavnog pregleda odlučili da neće proučiti podatke iz znanstvenih časopisa (kako se inače rade sustavni pregledi) već iz dokumentacije nastale tijekom postupka dobivanja odobrenja za stavljanje lijekova na tržište. Ti su podaci dobiveni od regulatornih tijela Velike Britanije, Sjedinjenih Američkih Država, Europske agencije za lijekove, Japana, a dobivena su i izvješća o kliničkih ispitivanja proizvođača navedenih lijekova (nakon dugotrajne medijske kampanje). To je autorima sustavnog pregleda omogućilo provjeru podataka iz randomiziranih placebo-kontroliranih kliničkih ispitivanja provedenih u odraslih i djece s potvrđenom ili sumnjom na prirodnu izloženost gripi.

Autori su nakon procjene oko 160.000 stranica regulatornih dokumenata zaključili kako postoje značajni problemi u ustroju i provedbi ispitivanja, prikazu rezultata i dostupnosti podataka iz mnogih kliničkih ispitivanja.

Što je pronađeno?

U sustavnom pregledu korišteni su podatci 46 kliničkih ispitivanja (20 u kojih je primijenjen oseltamivir i 26 u kojih je primijenjen zanamivir). Uočeni su problemi u ustroju mnogih uključenih kliničkih ispitivanja, što je utjecalo na pouzdanost u rezultate. Oba lijeka smanjuju trajanje simptoma gripe manje od jednog dana. Oseltamivir nije imao utjecaj na broj hospitalizacija, temeljem podataka svih ljudi koji su sudjelovali u kliničkim ispitivanjima oseltamivira. Klinička ispitivanja zanamivira nisu bilježila navedeni ishod. Učinci na upalu pluća i druge komplikacije gripe (kao bronhitis, upala srednjeg uha i upala sinusa) nisu pouzdano opisivani, što je vidljivo iz test-lista ispitanika u dokumentaciji kliničkih ispitivanja. Ukazano je na ograničenja dijagnostičkih kriterija za upalu pluća. Regulatorna tijela uočila su nedostatak u dnevnicima ispitanika tijekom njihova praćenja. Kod djece s astmom nije bilo jasnog učinka na vrijeme potrebno do prvog ublažavanja simptoma gripe.

Klinička ispitivanja u prevenciji gripe pokazala su da oseltamivir i zanamivir smanjuju rizik simptomatske gripe u pojedinaca i ukućana. Nema dokaza učinkovitosti na gripu bez simptoma ili na bolest sličnu gripi, ali uočeni problemi u provedbi kliničkih ispitivanja onemogućavaju donošenje konačnog zaključka.

Oseltamivir je povezan s nastankom mučnine, povraćanja, glavobolje, bubrežnih i psihijatrijskih događaja; zadnje tri nuspojave pojavile su se nakon korištenja lijeka u svrhu sprječavanja gripe (profilaksa). Nejasan je učinak na srce: ispitivani lijekovi mogu smanjiti srčane simptome, ali mogu dovesti do ozbiljnih problema srčanog ritma. Terapijska klinička ispitivanja zanamivirom u odraslih nisu dovela do povećanog rizika neželjenih događaja. Nedostatni su dokazi mogućeg štetnog djelovanja u terapijskim kliničkim ispitivanjima zanamivirom u djece.

Podudarnost s procjenom drugih tijela

Nedostatak prikladnih dokaza koji pokazuju učinak na komplikacije gripe slaže se sa zaključkom Američke agencije za hranu i lijekove (FDA). FDA dozvoljava tvrdnju učinkovitosti oba lijeka za prevenciju i liječenje simptoma gripe, ali ne i ostale učinke uključujući prekid prijenosa širenja virusa gripe između osoba ili prevencije upale pluća. FDA opisuje sveukupno djelovanje oba lijeka kao umjereno.

Mehanizam djelovanja blagotvornih učinaka

Ovi rezultati pokazuju da snižen imunološki odgovor s niskom razinom tvari koje potiču upalu (proinflamatornih citokina) pod utjecajem oseltamivir karboksilata može smanjiti simptome gripe neovisno o zaustavljanju umnažanja virusa gripe. Mogući učinak oseltamivira na smanjenje temperature (hipotermički ili antipiretički učinak) na središnji živčani sustav može doprinijeti ublažavanju simptoma. Tvrdnja da oseltamivir ima učinak na prekid širenja virusa i smanjenje komplikacija nije potkrijepljena dostupnim podatcima.

Predloženi mehanizam djelovanja sa strane proizvođača specifičan za virus gripe ne podudara se s kliničkim dokazima koji upućuju na sustavno i centralno djelovanje.

Bilješke prijevoda

Cochrane Hrvatska
Prevela: Mirjana Huić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Резюме на простом языке

Регуляторная информация о клинических испытаниях осельтамивира (Taмифлю) и занамивира (Реленза) при гриппе у взрослых и детей

Осельтамивир и занамивир были складированы во многих странах для лечения и профилактики сезонного и пандемического гриппа, [чтобы использовать] до того как вакцина против гриппа, соответствующая циркулирующему вирусу, станет доступной. Осельтамивир классифицируется Всемирной организацией здравоохранения как основное (жизненно-важное) лекарственное средство.

Какие подходы к этому обзору использовались

Мы обновили и объединили наши обзоры по противовирусным средствам занамивир и осельтамивир при гриппе у взрослых и детей на основании отчетов производителей в регуляторные органы (отчеты о клинических исследованиях) и комментариев регуляторов. Мы назвали эти комментарии и отчеты "регуляторная информация'. Отчеты о клинических исследованиях не опубликованы, это обширные документы с очень подробными деталями испытаний, которые сформировали базу для маркетингового одобрения. Они включают в себя протоколы, методы и результаты. Отчеты о клинических исследованиях до сих пор были конфиденциальными, их видели только производители и регуляторы.

Почему мы предприняли этот подход

В предыдущих версиях этого обзора мы выявили неразрешенные несоответствия в данных, представленных в опубликованных отчетах по клиническим испытаниям, и существенную предвзятость публикаций (публикационное смещение). Исходя из этого, мы решили не использовать данные из журнальных статей, а включили документы, созданные во время процессов лицензирования (маркетингового одобрения). Мы получили доступ к таким данным из Великобритании, США, Европейского лекарственного агентства (EMA), от японских регуляторов и к отчетам по клиническим исследованиям от производителей (после затяжной кампании в средствах массовой информации). Это позволило нам проверить информацию из рандомизированных плацебо-контролируемых клинических испытаний на взрослых и детях с подтвержденным или предполагаемым контактом с естественно встречающимся гриппом.

Исходя из наших оценок регуляторных документов (более 160 000 страниц), мы пришли к выводу, что были существенные проблемы с дизайном, проведением, отчетностью и доступностью информации во многих из этих клинических испытаний.

Что мы нашли

Мы использовали в этом обзоре данные из 46 клинических испытаний (20 по осельтамивиру и 26 исследований по занамивиру). Мы определили проблемы в дизайне многих исследований, которые мы включили, и которые отразились на нашей уверенности в их результатах. Мы обнаружили, что оба лекарства сокращали продолжительность симптомов гриппоподобного заболевания (неподтвержденный грипп или "грипп") менее, чем на один день. Осельтамивир, на основании данных от всех людей, включенных в клинические испытания по лечению осельтамивиром, не влиял на число госпитализаций. Клинические испытания по занамивиру этот исход не регистрировали. Сообщения о влиянии на пневмонии и другие осложнения гриппа, такие как бронхит, инфекции среднего уха (средний отит) и синуситы, были не надёжны, как показали истории болезни по документам клинического испытания. Некоторые формы показали ограничения (проблемы) диагностических критериев пневмонии. Регуляторные комментарии отметили проблемы с недостающими дневниками наблюдения у участников. У детей с астмой не было ясного влияния на время до первого облегчения симптомов.

Клинические испытания по профилактике (заболевания) показали, что осельтамивир и занамивир снижали риск симптоматического гриппа у отдельных лиц и в семье. Не было доказательств влияния на бессимптомный грипп или на не грипп, на гриппоподобные заболевания, но проблемы в проведении испытаний препятствуют любому определённому заключению.

Применение осельтамивира было связано с тошнотой, рвотой, головными болями, почечными и психиатрическими событиями; последние три случались, когда его [осельтамивир] применяли для профилактики гриппа. Его [осельтамивира] действие на сердце остается неясным: он может уменьшать симптомы со стороны сердца, но может и вызывать серьезные проблемы сердечного ритма. В клинических испытаниях занамивира у взрослых не было повышенного риска по сообщённым неблагоприятным событиям. Свидетельства возможного вреда, связанного с лечением детей занамивиром, были разрозненные.

Соответствие другим результатам

Отсутствие качественных доказательств, демонстрирующих влияние на осложнения [гриппа], согласуется с осторожными выводами по обоим лекарствам, сделанными Администрацией по контролю за лекарствами и пищевыми продуктами США (FDA). FDA разрешила заявления только по эффективности обоих лекарств в профилактике и лечении симптомов гриппа, но не по другим эффектам (в том числе прерывание распространения вируса от человека к человеку или профилактика пневмонии). FDA описала эффективность обоих препаратов в целом, как "скромную".

Механизм развития благоприятных эффектов

Эти результаты позволяют предположить, что низкий иммунный ответ с низким уровнем прововоспалительных цитокинов, вызванный действием осельтамивира карбоксилата, может уменьшать симптомы гриппа, не связанные с подавлением размножения (репликации) вируса гриппа. Потенциальный гипотермический или жаропонижающий эффект осельтамивира как депрессанта центральной нервной систем, также может вносить вклад в очевидное сокращение симптомов пораженного организма. Заявления о способности осельтамивира прерывать передачу [от человека к человеку] вируса и уменьшать осложнения не поддерживаются никакими данными, к которым мы имели доступ.

Механизм действия, предложенный производителем, (специфичный для вируса гриппа) не соответствует клиническим доказательствам, что позволяет предполагать мультисистемное и центральное действие.

Заметки по переводу

Перевод: Абакумова Татьяна Рудольфовна. Редактирование: Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Казанский федеральный университет - аффилированный центр в Татарстане Северного Кокрейновского Центра. По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: lezign@gmail.com

Resumo para leigos

Informação regulatória dos estudos com oseltamivir (Tamiflu) e zanamivir (Relenza) para influenza em adultos e crianças

O oseltamivir e o zanamivir vêm sendo estocados em vários países para o tratamento e prevenção da influenza sazonal e pandêmica, antes de uma vacina adequada para o vírus circulante se tornar disponível. O oseltamivir é classificado pela Organização Mundial da Saúde como um medicamento essencial.

Como esta revisão foi realizada

Nós atualizamos e combinamos as nossas revisões sobre as drogas antivirais zanamivir e oseltamivir para influenza em adultos e crianças com base nos relatos dos fabricantes para os órgãos regulatórios (relatos de estudos clínicos) com os comentários dos órgãos regulatórios. Nós chamamos esses comentários e relatos como “informação regulatória”. Os relatos de estudos clínicos são documentos extensos e não publicados, com excelentes detalhes sobre os estudos que formaram a base para a aprovação das drogas no mercado. Eles incluem protocolos, métodos e resultados. Até recentemente, os relatos de estudos clínicos eram confidenciais, acessíveis apenas a fabricantes e agências regulatórias.

Porque nós escolhemos esta conduta

Nas versões anteriores desta revisão, identificamos divergências não resolvidas nos dados apresentados nos relatos dos estudos publicados, e viés de publicação importante. Como consequência, optamos por não usar os dados de artigos publicados; preferimos incluir os documentos gerados durante o processo de licenciamento desses medicamentos. Nós avaliamos os dados de órgãos regulatórios do Reino Unido, Estados Unidos, Europa, Japão e relatos de estudos clínicos dos fabricantes (depois de uma longa campanha na mídia). Isso nos permitiu verificar os dados contidos em estudos randomizados e placebo-controlados em adultos e crianças com exposição confirmada ou suspeita à influenza que ocorre naturalmente.

Com base nas nossas análises dos documentos regulatórios (com mais de 160.000 páginas), nós concluímos que, em muitos dos ensaios clínicos, houve problemas substanciais com o desenho, condução, relato e disponibilidade da informação.

O que nós encontramos

Nós utilizamos os dados de 46 estudos (20 estudos com oseltamivir e 26 com zanamivir) nesta revisão. Identificamos problemas no desenho de vários estudos que nós incluímos, o que afeta a confiabilidade dos resultados. Encontramos que as duas drogas diminuem a duração dos sintomas da doença parecida com influenza (influenza não confirmada ou “gripe”) em menos de um dia. O oseltamivir não mudou o número de internações, com base nos dados de todas as pessoas que participaram de estudos de tratamento com oseltamivir. Os estudos com o zanamivir não relataram esse desfecho. Os efeitos desses remédios sobre a pneumonia e outras complicações da influenza, como bronquite, infecção do ouvido médio (otite média) e sinusite, não foram descritos de forma confiável, conforme pudemos ver nos formulários de relato de caso dos documentos do estudo. Alguns formulários eram limitados no critério de diagnóstico para pneumonia. Os comentários regulatórios notaram problemas de falta de diários de seguimento para participantes com pneumonia. Nas crianças com asma, não houve efeito claro no tempo para o primeiro alívio dos sintomas.

Os estudos de profilaxia mostraram que o oseltamivir e o zanamivir reduziram o risco de influenza sintomática em indivíduos e em domicílios. Não houve evidência de efeito sobre influenza assintomática ou sobre doenças parecidas com influenza, mas que não são influenza, mas os problemas de condução dos estudos impediram que fosse tirada qualquer conclusão definitiva.

O uso do oseltamivir foi associado com náusea, vômito, dores de cabeça, eventos renais e psíquiátricos; estes últimos três ocorreram quando foi usado para prevenir a influenza (profilaxia). O seu efeito no coração é incerto: pode reduzir os sintomas cardíacos, mas pode induzir a sérios problemas de ritmo cardíaco. Nos estudos de tratamento com zanamivir em adultos, não houve risco aumentado de eventos adversos. Existe pouca evidência sobre possíveis danos associados ao tratamento com zanamivir em crianças.

Concordância com outros achados

A falta de boas evidências demonstrando efeito nas complicações concorda com as conclusões conservadoras sobre as duas drogas apresentadas pelo US Food and Drug Administration (FDA). O FDA somente autorizou alegações de efetividade das duas drogas para a prevenção e tratamento dos sintomas da influenza e não para outros efeitos (incluindo a interrupção da transmissão do vírus da influenza de pessoa para pessoa ou a prevenção de pneumonia). O FDA descreveu o desempenho geral das duas drogas como sendo “modesto”.

Mecanismos de ação para efeitos benéficos

Esses achados sugerem que a baixa resposta imunológica, com baixos níveis de citocinas pró-inflamatórias, que é induzida pela ação do carboxilato de oseltamivir, pode reduzir os sintomas da influenza não relacionados com a inibição da replicação do vírus. O efeito hiportérmico potencial ou antipirético do oseltamivir como depressor do sistema nervoso central pode contribuir com a redução aparente dos sintomas do doente. Declarações feitas sobre a capacidade do oseltamivir de interromper a transmissão viral e reduzir os sintomas não são apoiadas por nenhum dado ao qual nós tivemos acesso.

O mecanismo de ação proposto pelos fabricantes (específico para o vírus da influenza) não se enquadra à evidência clínica, que sugere uma ação central e em diversos sistemas.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Maíra Tristão Parra).

淺顯易懂的口語結論

成人與兒童流感的oseltamivir (Tamiflu)及zanamivir (Relenza)試驗法規資訊

在取得與流行病毒吻合的流感疫苗前,很多國家會儲備oseltamivir跟zanamivir來治療與預防季節性及傳染性的流感,世界衛生組織將oseltamivir列為不可缺少的藥品。

如何進行本文獻回顧

我們根據製造商給主管機關的報告(臨床研究報告)與主管機關的評論,修正並結合有關成人及兒童流感抗病毒藥zanamivir與oseltamivir的文獻。我們稱這些評論與報告為「法規資訊」。臨床研究報告為未發表、範圍廣泛且富含詳盡試驗細節的文件,是構成市場認可的根基,包括研究協定、方法及結果。直至今日,臨床研究報告仍是機密,只有製造商與主管機關看過。

我們為何採取這個方式

在之前的文獻裡,我們在已發表的試驗報告資料中,找到未解決的差異與大量的出版偏誤。我們因而選擇不要採用期刊文章裡的資料,改收錄在許可程序中產生的資料。我們由英國、美國、歐洲藥物管理局(EMA)、日本主管機關以及來自製造商的臨床研究報告(長期的媒體宣傳之後)取得資料,讓我們得以驗證來自成人及兒童已確診或疑似暴露在自然產生的流感中之隨機安慰劑對照試驗資料。

根據我們對法規文件(超過160,000頁)的評估,得到的結論是,許多試驗的設計、執行、記錄以及資訊的可得性有相當多的問題。

我們發現了什麼

本文獻中我們採用來自46個試驗(20個oseltamivir研究與26個 zanamivir研究)的資料。在收錄的許多研究中找出了研究設計的問題,影響我們對結果的信賴。我們發現兩種藥品對類流感(未確診的流感或流行性感冒)症狀期的縮短天數不到1天。根據由所有參與oseltamivir 試驗的人得到的資料顯示,oseltamivir對住院人數沒有影響,zanamivir試驗則沒有記錄這項結果。誠如試驗資料的個案記錄表所示,對於肺炎與其他流感併發症如支氣管炎、中耳感染(中耳炎)及鼻竇炎的影響記錄是不可靠的,有些記錄顯示肺炎診斷標準的限制。主管機關的評論注意到受試者追蹤日誌遺失的問題。對於有氣喘的兒童,到初次症狀緩解所需時間沒有明確的影響。

預防試驗顯示在個人與家庭中,oseltamivir與zanamivir降低了感染症狀性流感的風險。沒有對於無症狀流感或非流感、類流感影響的證據,但試驗執行的問題阻礙了任何明確的結論。

Oseltamivir的使用與噁心、嘔吐、頭痛、腎臟及精神相關的事件有關,其中後三項出現在使用oseltamivir來預防流感的時候(預防)。它對心臟的影響仍不明確,可能減低心臟相關的症狀,但也可能導致嚴重的心律問題。成人的zanamivir治療試驗沒有增加不良事件的記錄,少有與兒童zanamivir治療有關的可能危害之證據。

與其他發現的一致性

缺少顯示對於併發症影響的良好證據與美國食品藥物管理局(FDA)提出的、與兩種藥品有關的保守結論一致;FDA只認可兩種藥品對預防及治療流感症狀有效的說法,不承認其他效應(包括阻礙流感病毒在人與人之間傳播或預防肺炎)。FDA描述兩種藥品的整體效能為「適當」。

有益效應的作用機轉

這些發現全都指出,由oseltamivir carboxylate引發的低免疫反應與低階促發炎細胞激素,可能減輕與流感病毒複製的抑制作用無關的流感症狀。以oseltamivir做為中樞神經系統抑制劑的潛在低溫或退熱效應,可能也有助於主要症狀明顯減少。有關oseltamivir干預病毒傳播及減少併發症的能力之陳述,不被任何我們能取得的資料所支持。

由製造商提出的作用機轉(流感病毒特異)與臨床證據不符,顯示多系統與核心作用。

譯註

翻譯者:臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

概要

奥司他韦(Tamiflu)和扎那米韦(Relenza)治疗成人和儿童流行性感冒的试验监管信息

在出现可用的与流行病毒相匹配的流感疫苗之前,奥赛他韦和扎那米韦已被许多国家储备用于治疗和预防季节性和大流行性流感。奥司他韦被世界卫生组织列为基本药物。

该综述如何进行

我们根据制造商向监管机构的报告(临床研究报告)和监管机构的意见,对成人和儿童流感的抗病毒药物扎那米韦和奥司他韦进行了更新和综合评估。我们称这些评论和报告为“监管信息”。临床研究报告为未发表的、有广泛且丰富的细节信息的文件,是构成市场认可的基础,包括方案,方法和结果。直至今日,临床研究报告仍是保密的,只有制造商和监管机构才能看到。

为什么采用这种方法

在本综述的之前版本中,根据已发表的试验报告提供的数据,我们发现存在无法解决的差异及实质性的发表偏倚。因此,我们选择不使用期刊发表文献中的数据,而是纳入药品许可申请过程中产生的资料。我们已经从英国,美国,欧洲药品管理局,日本监管机构和制造商的临床研究报告(经过长时间的媒体宣传)中获得了这些数据。这使我们能够验证来自成年人或儿童已确诊或疑似暴露于自然流行性感冒中的随机、安慰剂对照试验的信息。

根据我们对监管文件(超过16万页)的评估,得出的结论是,许多试验的设计,实施,报告和信息可及性存在严重问题。

我们发现了什么

本研究中我们采用了来自46项试验的数据(20项奥司他韦和26项扎那米韦研究)。在纳入的许多研究中存在一些设计问题,这影响了我们对其结果的信心。我们发现两种药物都缩短了流感样症状(未确诊的流感或“流感”)的持续时间,缩短程度少于1天。根据所有参与奥司他韦治疗试验者的数据,奥司他韦对住院人数没有影响。扎那米韦试验没有记录这一结果。对肺炎和其他并发症如支气管炎,中耳感染(中耳炎)和鼻窦炎的影响的报告是不可靠的,因为数据来源于试验资料中的病例报告表。有些记录显示肺炎的诊断标准存在局限性。监管评论指出受试者缺少后续日记卡随访的问题。对哮喘儿童首次症状缓解所需时间无明显影响。

预防性试验表明,奥司他韦和扎那米韦降低了个人和家庭罹患症状性流感的风险。没有证据显示对无症状流感或非流感样或流感样疾病有疗效,但是试验执行中存在的问题也使得无法得出明确的结论。

奥司他韦的使用与恶心,呕吐,头痛,肾脏和精神事件有关,其中后三种是用于预防流行性感冒时出现的(预防)。它对心脏的影响不清楚:它可能会减轻心脏症状,但也可能会引起严重的心律问题。在扎那米韦的成人治疗试验中,没有增加不良事件的记录。关于儿童扎那米韦治疗儿童相的可能危害的证据很少。

与其他发现的一致性

缺少显示对于并发症影响的良好证据,与美国食品和药物管理局(FDA)提出的关于两种药物的保守结论一致。FDA只认可两种药物用于预防和治疗流行性感冒症状的有效性声明,而不是其他疗效(包括中断流感病毒的人对人之间传播或预防肺炎)。FDA将两种药物的整体效能描述为“适度”。

疗效的作用机制

这些发现都表明,通过奥司他韦羧酸盐的作用诱导的低水平的促炎细胞因子的低免疫应答可能减轻与抑制流感病毒复制无关的流感症状。奥司他韦作为中枢神经系统抑制剂具有潜在的降温或解热作用,这也可能导致宿主症状的明显减轻。我们能够获得的任何数据不支持奥司他韦在中断病毒传播和减少并发症方面的作用。

制造商提出的作用机制(流感病毒特异性)与临床证据不符,显示多系统与核心作用。

翻译注解

译者:李文元,审校:梁宁。北京中医药大学循证医学中心2017年6月28日

Background

This review (known as A159) reports our efforts to get to the bottom of the issue of the effects of NIs by appraising evidence from unpublished clinical study reports (see Glossary, Appendix 1) and regulatory documents containing comments and reviews. We have called the body of clinical studies and regulatory comments 'regulatory information'. For the history and evolution of the review see Appendix 2.

Description of the condition

Influenza is mostly a mild, self limiting infection of the upper airways with local symptoms, including sniffles, nasal discharge, dry cough and sore throat, and systemic symptoms such as fever, headache, aches and pains, malaise and tiredness.

Occasionally patients with influenza develop complications such as pneumonia, otitis media and dehydration or encephalopathy with or without liver failure, which may be due to the effects of the influenza virus itself or associated secondary bacterial infections and/or adverse effects of drugs such as antipyretics (including salicylates and other non-steroidal anti-inflammatory drugs) (Hama 2008).

Influenza is not clinically distinguishable from influenza-like illness (ILI) (Call 2005). Epidemic influenza in humans is caused by influenza A and B viruses. Currently, influenza A/H1N1, influenza A/H3N2 and influenza B cause most influenza infections worldwide (CDC 2013).

Description of the intervention

Neuraminidase inhibitors (NIs) comprise inhaled zanamivir (Relenza, GlaxoSmithKline), oral oseltamivir (Tamiflu, Gilead Sciences and F. Hoffman-La Roche), parenteral peramivir (BioCryst Ltd), inhaled laninamivir (Daiichi Sankyo Co. Ltd) (Sugaya 2010) and others still under development (Hayden 2009). The use of NIs has increased dramatically since the outbreak of A/H1N1 in April 2009, partly because of the rise in amantadine/rimantadine resistance and, in the early stages of the outbreak, the lack of a vaccine, which meant that NIs became a widespread public health intervention. The World Health Organization (WHO) had previously encouraged member states to stockpile and gain experience of using NIs (WHO 2002a; WHO 2002b; WHO 2004).

How the intervention might work

Although NIs may reduce the ability of the virus to penetrate the mucus in the very early stage of infection (Bhatia 2007; Matrosovich 2004; Moscona 2005; Ohuchi 2006), their main mechanism of action is thought to lie in their ability to inhibit influenza viruses from exiting host cells (Liu 1995; Moscona 2005). The manufacturers state that oseltamivir does not prevent infection, nor affect antibody production (Smith 2006), but it reduces symptom duration probably by reducing viral load, spread and release of cytokines (Hayden 1999; WV15670), diminishing the chance of complications and interrupting person-to-person viral spread.

Oseltamivir phosphate (Tamiflu) is the pro-drug of oseltamivir carboxylate, the effective form. Oseltamivir phosphate dissociates in the gastrointestinal tract to form oseltamivir, which is absorbed and metabolised into oseltamivir carboxylate by hepatic carboxylesterase (h-CE). Oseltamivir may have a central depressant action (Hama 2008) and may also inhibit human sialidase (Li 2007), causing abnormal behaviour.

Inhaled zanamivir reaches a far lower plasma concentration compared to its intravenous administration (Cass 1999).

Any treatment that reduces the complications of influenza (for example, pneumonia) and the excretion of the virus from infected people might be a useful public health measure to contain an epidemic by limiting the impact and spread of the virus. In addition to symptomatic treatment, prophylactic use for interrupting the spread of disease has informed pandemic planning over the past decade.

Why it is important to do this review

There are three major reasons for conducting this review, in addition to questions of efficacy associated with the clinical use of NIs for influenza:

  1. Influenza antivirals are a commonly used and stockpiled drug against past and future pandemics on the basis of international and national recommendations. These recommendations are based on the claimed and assumed ability of the drug to reduce complications and transmission (HHS 2005; WHO 2007). In theory, containing the spread of influenza allows time for an organised response with longer-term interventions (such as vaccines), which take time to produce (WHO 2007).

  2. There are legitimate reasons to doubt these claims and the results of previous Cochrane reviews of NIs in adults (Jefferson 2006; Jefferson 2009a) and children (Shun-Shin 2009), due to the risk of reporting bias, including the certainty of publication bias (Doshi 2012a; Doshi 2012b).

  3. Oseltamivir is now on the list of WHO essential drugs (WHO 2013a; WHO 2013b).

Process

A159 is an amalgamation of two long-standing Cochrane reviews on the effects of NIs for influenza in healthy adults (Jefferson 2010a, also published as Jefferson 2009a) and children (Matheson 2007), and it is based on the assessment of trials through their clinical study reports and other regulatory information: a decision we made after finding substantial reporting bias in the journal publications of the relevant trials.

For the rationale for this process see Appendix 2.

Examples of discrepancies and reporting bias

We identified that 60% (3145/5267) of patient data from randomised, placebo-controlled, phase III treatment trials of oseltamivir have never been published. This includes M76001, the biggest treatment trial ever undertaken on oseltamivir (with just over 1400 people of all ages). Exclusion of unpublished data changed our previous findings regarding the ability of oseltamivir to reduce the complications of influenza (Doshi 2009; Jefferson 2009a). In some cases, mistakes in the attribution of adverse events were only discovered through matching summary tables with individual participant listings (Gravenstein 2013; Peters 2001; WV15825).

A modified approach

We have modified the routine Cochrane processes to improve our previous methods, which we now consider inadequate. To resolve inconsistencies and under-reporting, we changed our approach by no longer including trial data as reported in papers published in biomedical journals. Instead, we treated clinical study reports as our basic unit of analysis. Clinical study reports are often sent to national drug regulators such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) (formerly EMEA), which require far more stringent standards for completeness and accuracy of reporting than biomedical journals. Journal articles can be regarded as a very succinct synthesis of a clinical study report. In addition to seeking clinical study reports, we decided to read and review regulatory documentation. The FDA in particular (and the EMA to a far lesser extent) make many of its scientific reviews available on its website. Unlike Cochrane review authors, regulators can have access to the whole data set and their comments can provide useful insight, helping to achieve a better understanding of trial programmes.

Clinical study reports generally remain hidden from public view and are not readily available for wider scientific scrutiny, despite the wealth of information they contain for those willing and able to spend the time reading them and despite calls to make all relevant trial data public (Doshi 2013; Godlee 2009), as well as the known problems with reporting biases (McGauran 2010; Wieseler 2013).

Implications

This modified approach to a Cochrane review aims to provide patients, clinicians and policy-makers with the most transparent and independent information possible about NIs for influenza. In addition, it should contribute to improving a European regulatory and pharmacovigilance legal framework, which commentators consider weak (Cohen 2009; Godlee 2009). We believe that as NIs have become public health drugs, recommended and stockpiled globally, independent scrutiny of all the evidence relating to harms and effects on complications is necessary to provide patients, policy-makers and physicians with a complete and unbiased view of their risks and benefits.

Implication for A/H1N1 (2009) influenza

In response to our 2010 review (Jefferson 2009a; Jefferson 2010a), some have argued that its findings cannot be applied to the 2009 A/H1N1, suggesting that it is a new virus and thus we need new evidence (JAID 2010; Maugh 2009; Nebehay 2009; NHS 2009; NHS 2010). Novel A/H1N1 is a new strain of a subtype that has been circulating since 1977, but it also resembles the A/H1N1 strain that has been circulating since before 1957 (CDC 2009) or before the 1918 pandemic (Itoh 2009). Influenza subtype A/H1N1 was indeed circulating in the clinical trials we have included in our previous reviews. In addition, oseltamivir and zanamivir were approved by regulators worldwide for the treatment and prevention of influenza types A and B, not specific subtypes or strains of influenza A and B. The expectation of regulatory approval is thus that the effects of these drugs demonstrated in clinical trials will apply to future strains of influenza A and B. Use of these drugs during the pandemic was not off-label. It was approved use because of the assumption that the clinical trial evidence underpinning regulatory approval applied to novel A/H1N1. We reviewed the clinical trial evidence with the expectation that our results, similar to regulators, will apply to all influenza viruses.

Wider implications

The modified approach in this Cochrane review grew out of a realisation that prior methods employed to review NIs were inadequate. There seems to be no compelling reason to think that the lessons learned are limited to these particular drugs (Godlee 2009; Rodgers 2013; Vedula 2009; Vedula 2013; Wieseler 2013). For this reason, our independent scrutiny, using all possible trial information, may inform both the wider debate on the adequacy of existing regulatory frameworks in the adoption of new drugs and the question of whether other systematic reviews should move to this new, more rigorous, approach, which focuses on trial programmes rather than single trials (Eyding 2010; Ioannidis 2010) (see Glossary, Appendix 1). Although there is substantial evidence for the effects of reporting bias in estimates of effectiveness, less is known of its impact on the evidence of harms (Chou 2005). We decided to quantify the additional resources required to follow our modified methodological approach to assess the feasibility of other systematic reviews proceeding in a similar fashion.

See the Differences between protocol and review section for the previous version of the objectives of this review.

Objectives

To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments.

Methods

Criteria for considering studies for this review

Types of studies

We included evidence from randomised controlled trials (RCTs) testing the effects of NIs for prophylaxis, post-exposure prophylaxis (PEP) and treatment of influenza. Prophylaxis is the mode of use of NIs when there is expectation of possible near-future exposure to influenza. PEP is the use of NIs following probable exposure to influenza but before symptoms develop. Treatment is the use of NIs in persons showing probable signs of influenza.

Due to discrepancies between published and unpublished reports of the same trials, we decided to include only those trials for which we had unabridged clinical study reports (for example, with consecutively numbered pages), even though they may be parts of clinical study reports (i.e. Module 1 only) and information on reports of trials that were considered "pivotal" (i.e. first or second-line evidence to regulators in support of the registration application).

Types of participants

We included previously healthy people (children and adults). 'Previously healthy' includes people with chronic illness (such as asthma, diabetes, hypertension), but excludes people with illnesses with more significant effects on the immune system (such as malignancy or HIV infection). We included only trials on people exposed to naturally occurring influenza with or without symptoms. We targeted the intention-to-treat (ITT) and safety populations as our prior review discovered compelling evidence that the intention-to-treat-influenza-infected (ITTI), the sub-population deemed to be influenza-infected, were not balanced between treatment groups in the Roche oseltamivir trials. In addition, estimates from the ITT population will be more generalisable to clinical practice, where routine testing for influenza is not common in many countries (and even where used, remains of variable accuracy).

Types of interventions

NIs administered by any route compared with placebo during the period in which medication was assumed and during the follow-up (on- and off-treatment: on-t and off-t) periods.

Types of outcome measures

Primary outcomes
Primary outcome measures for treatment studies
  1. Symptom relief

  2. Hospitalisation and complications

  3. Harms

Primary outcome measures for prophylaxis studies
  1. Influenza (symptomatic and asymptomatic, always with laboratory confirmation) and influenza-like illness (ILI)

  2. Hospitalisation and complications

  3. Interruption of transmission (in its two components, reduction of viral spread from index cases and prevention of onset of influenza in contacts)

  4. Harms

Secondary outcomes
Secondary outcome measures for treatment studies
  1. Symptom relapse after finishing treatment

  2. Drug resistance

  3. Viral excretion

  4. Mortality

Secondary outcome measures for prophylaxis studies
  1. Drug resistance

  2. Viral excretion

  3. Mortality

Whilst overall symptom reduction is well documented, our interest was particularly focused on complications and adverse events, as this is where evidence is currently scarce or inconclusive (Jefferson 2009a; Shun-Shin 2009). Our preliminary examination of some regulatory documents and some published versions of the studies had identified that some symptoms and sequelae of influenza (such as pneumonia) had been classified as either a 'complication of influenza' or as an 'adverse event of the treatment', or both. This is somewhat confusing and we intended to analyse 'compliharms' (see Glossary, Appendix 1) irrespective of the classification as a 'complication of influenza' or as an 'adverse event of the treatment' (Appendix 3) in oseltamivir trials. Complications of particular interest included pneumonia, bronchitis, otitis media and sinusitis as these were the secondary illnesses often collected in the Roche oseltamivir trials and we agreed that these events are clinically important. Initially we constructed a table to illustrate the design methodology used for each complication by study (Table 1). The table included the following variables: definition of which events are termed complications; where complications are first defined in the clinical study report; diagnosis method; and availability of data. We then stratified our analysis by method of diagnosis with three possible criteria: (1) laboratory-confirmed diagnosis (e.g. based on radiologically or microbiologically confirmed evidence of infection); (2) clinical diagnosis without laboratory confirmation (diagnosed by a doctor after a clinical examination); (3) other type of diagnosis such as self reported by patient. We conducted analysis of any complication (pneumonia, bronchitis, otitis media and sinusitis) that was classified as serious or led to study withdrawal.

Table 1. Blank case report forms' data capture for secondary illnesses in oseltamivir trials
  1. #Events within the first 2 days of the study were excluded
    *Note that some events are reported as secondary illness and adverse event (AE) but some events are reported as secondary illness only and some events are reported as adverse event only
    BRON = bronchitis
    CRF = case report form
    CXR = chest x-ray
    ECG = electrocardiogram
    LRTI = lower respiratory tract infection
    MRI = magnetic resonance imaging
    OM = otitis media
    PNUM = pneumonia
    px = prescription
    ˜RAP = reporting analysis plan
    SIN = sinusitis

Study Where in CRF (PDF pg #) Data captured

Person reporting

(participant/investigator)

Where reported Specific field for recording confirmatory assessment (e.g. CXR) Confirmation (including px)
M760011167

Yes/no answer to question: "Is this event a secondary illness related to influenza?"

Secondary illness is defined: sinusitis, otitis, bronchitis, pneumonia + other chest infections that are not diagnosed as bronchitis and/or pneumonia

InvestigatorIn form for "Adverse events or intercurrent illness"NoPx
NV16871361, 389

Form states:

Have there been any changes in the patient’s health including any new conditions or worsening of existing conditions since day 1 (please include secondary illnesses)?

Yes/No. If "Yes", please record the details on the "Adverse events or secondary illness" form in the Additional Forms section of the CRF on pg 30.0. All serious adverse events must be reported within 1 working day of occurrence to Roche

Pg 30.0 of CRF (PDF pg 389) defines secondary illnesses as sinusitis, otitis media, bronchitis and pneumonia, and asks additional questions such as relationship to test drug and outcome, and leaves space for investigator's comments on the adverse event

Investigator

Secondary illness not listed as efficacy outcomes

Recording of secondary illnesses was to occur in a form titled "Adverse event or secondary illness"

NoPx
WV15670732, 754, 791, 832

CRF form (PDF pg 732) states:

Secondary illness reminder

Has the patient reported any sinusitis, otitis, bronchitis, other chest infection or pneumonia since baseline?

yes [ ] Complete secondary illness page (not the adverse event page)

no [ ]

Secondary illness page CRF (PDF pg 754) requests information on date of onset, date resolved, whether treatment was given and, if so, what treatment or medical procedures, total daily dose, and start/end date of treatment or medical procedure

In addition, participants could fill in information related to a secondary illness in their diary card in the free-text box called "Notes" which prompts participants: "Please can you record below any extra information about your flu which may be of interest to us, (for example: did your flu symptoms re-occur, and if so when?), and have you taken any other treatments. If so please record the treatment name and the dates you took it." (PDF pg 791)

Participant mediated through Investigator

For investigators, on "Secondary illness" form

For participants, on "Notes" section of diary card

No 
WV15671740, 889, 1018

CRF form (PDF pg 740) states:

Secondary illness reminder

Has the patient reported any sinusitis, otitis, bronchitis, other chest infection or pneumonia since baseline?

yes [ ] Complete secondary illness page (not the adverse event page)

no [ ]

Secondary illness page CRF (PDF pg 889) requests information on date of onset, date resolved, whether treatment was given and, if so, what treatment or medical procedures, total daily dose and start/end date of treatment or medical procedure

Secondary illnesses are listed as sinusitis, otitis, bronchitis, pneumonia and other chest infections that are not diagnosed as bronchitis and/or pneumonia

In addition, participants could fill in information related to a secondary illness in their diary card in the free-text box called "Notes" which prompts participants: "Please can you record below any extra information about your flu which may be of interest to us, (for example: did your flu symptoms re-occur, and if so when?), and have you taken any other treatments. If so please record the treatment name and the dates you took it." (PDF pg 1018)

Participant mediated through investigatorMentioned in M1 and RAP as tertiary outcomes not mentioned in protocolNoPx
WV15673/WV15697From 483No mention of pneumonia, secondary illness, complications in the CRFsUnclearSecondary illnesses not listed in protocol as endpoints. They are listed as safety endpoints in the RAP which states that "pre-defined" secondary illnesses were "sinusitis, otitis, bronchitis, pneumonia, and other chest infections that are not diagnosed as bronchitis and/or pneumonia, plus recurrence of symptoms from the diary card once alleviation had occurred." (PDF pg 479)  
WV15707From 98

Pg 117 Secondary illness reminder: Has the patient reported any sinusitis, otitis, bronchitis, other chest infection or pneumonia since baseline?

yes [] - Complete secondary illness page (not the adverse event page)

no []

Pg 131: Diagnostic procedures

1) Were there any diagnostic procedures or tests carried out since day 1 as a result of influenza or secondary illness that were not scheduled as part of protocol?
Yes

Type of diagnostic procedure or test

1 Chest X-rays, 2 ECG, 3 Bacterial culture, 4 Bronchoscopy, 5 Pulmonary function test, 6 Viral culture (other than influenza), 7 Blood tests (other than antibody sample), 8 Other specify

No

Secondary illness page CRF (PDF pg 158) requests information on date of onset, date resolved, whether treatment was given and, if so, what treatment or medical procedures, total daily dose and start/end date of treatment or medical procedure

Participant mediated through investigatorMentioned in RAP as tertiary endpoints pg 57-8YesPx
WV15708From 460

Secondary illness reminder at pg 474:

Has the patient reported any new episodes of sinusitis, otitis, bronchitis, other chest infection or pneumonia since screening?

yes [] ... Complete adverse event page

no []

"Adverse events" CRF collected data on date of onset, initial intensity, test drug adjustment, whether treatment was given (if so, what), most extreme intensity, relationship to test drug, outcome, whether it led to hospitalisation and a free-text line for recording "Comments on AE" (e.g. PDF pg 479)

Participant mediated through investigatorSecondary illness not mentioned in protocolNoPx
WV15730From 340

Secondary illness reminder:

Has the patient reported any sinusitis, otitis, bronchitis, other chest infection or pneumonia since baseline?

yes [] ... Complete secondary illness page (not the adverse event page)

no []

The secondary illness page is descriptive of dates and px

Participant mediated through investigatorListed as tertiary endpoints in RAP at pg 297NoPx
WV15758From 637

Has the patient reported any new adverse events or symptoms (including intercurrent illnesses and secondary illnesses)?

yes [] record in the adverse events/intercurrent illness section of the case

no [] report form

Diagnostic confirmation of otitis media from pg 648 onwards

Participant mediated through investigatorListed as secondary illnesses in core report Module 1-2 (pg 36)YesPx
WV15759/871From 665Has the subject reported any adverse events including secondary and intercurrent illnesses?Participant mediated through investigator

Secondary illnesses not mentioned in protocol, but secondary outcome in core report

Note: worth looking at comparisons 1.49 to 1.51 in RM5. No effect but in bronchitis this study has a more conservative effect than NV 16871 which has no definitions and no diagnostics

YesPx
WV15799From 642

Secondary illness defined as in M76001. There is a generic physical examination form at pg 704 including "lungs" normal/abnormal specify_______

At pg 709 has the patient reported any new AE including intercurrent or secondary illnesses yes/no. If y record the adverse events/intercurrent illness section of the CRF (noted at pf 746 on to be at the back of the CRF) with FULL HISTORY, PHYSICAL EXAMINATION AND DIAGNOSTIC WORK UP QUESTIONS FOR BRON+PNUM+LRTI+SIN+OM including questions about CXR, MRI, sputum etc.

InvestigatorProportion of contacts who are classified as having a secondary illness subsequent to a confirmed episode of influenza listed as tertiary endpointsYesPx
WV15812/872From 285

Has the patient reported any new adverse events or symptoms (including intercurrent illnesses and secondary illnesses)?

yes [] record in the adverse events/intercurrent illness section of the case

no [] report form

At pg 450-74 is DIAGNOSIS OF SECONDARY ILLNESS page which is very similar to the one at serial 10

EXHAUSTIVE list of diagnostic procedures

Participant mediated through investigatorListed as secondary tertiary in protocol at pg 252YesPx
WV15819/978/876From 412

Pg 437 (adverse event reminder):

Has the patient reported any new adverse events or symptoms (including intercurrent illnesses)?

yes [] record in the adverse events/intercurrent illness section of the case

no [] report form

In CRF pg 447 and 443 usual secondary illness reminder

From pg 471 DIAGNOSTIC OF SECONDARY ILLNESS. This is a one page list of diagnostics similar to that at serial 10. The question is: "Were there any diagnostic procedures or tests carried out since day 1 as a result of influenza or secondary illness that were not scheduled as part of protocol?" If yes list per serial 10

From pg 486 is a list of diagnostic tests

Participant mediated through investigatorSecondary illness listed as secondary (required antibiotics) and tertiary outcomes in core report and as an addition in protocol amendment at pg 21YesPx
WV15825From 389

There is a usual note: please go to diagnosis of secondary illness at back of CRF. Pg 487:

Is this event a secondary illness related to influenza?

DIAGNOSTIC OF SECONDARY ILLNESS

From pg 510-40 with exhaustive list of diagnostics as per serial 10

Participant mediated through investigator

Secondary illness listed as secondary outcomes in protocol pg 346

Secondary illnesses recorded on "Adverse events" CRF

YesPx
WV16277From 415Not foundNot foundSecondary illness not listed as efficacy outcomes  

In all cases of influenza complications reporting (pneumonia, bronchitis, sinusitis, otitis media) there is a variable degree of participant self reporting, of investigator mediation (for example, in writing down the details in the case report form) and lack of verification with investigations such as culture or imaging. The 'self reported, investigator-mediated, unverified' title is relevant to all complications but for brevity we use it as sparingly as possible.

For harms we were limited by the frequency of occurrence of the adverse events collected in the trials. Consequently we meta-analysed (1) all serious adverse events; (2) all adverse events leading to study withdrawal; (3) all withdrawals; (4) all adverse events within a clinical study report's defined body system; as well as (5) a small group of common adverse events as defined in the FDA drug label for oseltamivir. There were too few events to meta-analyse (1) deaths; (2) serious adverse events by body system; and (3) any events that had an overall incidence of less than 0.5%. We did not meta-analyse outcomes with fewer than 10 events in total. We conducted analyses separately for on-treatment and off-treatment periods. However, in two cases where (on-treatment) treatment effects were borderline statistically significant (prophylaxis with oseltamivir: renal body system on-treatment and psychiatric body system on-treatment), we conducted additional analysis combining on- and off-treatment periods to maximise statistical power. We conducted dose-response harms analysis for two treatment trials (WV15670 and WV15671) combined and one prophylaxis study (WV15673/WV15697), as these trials investigated the active agent at multiple doses. These studies included standard-dose and high-dose oseltamivir arms. For these analyses we used logistic regression, adjusting for study effects if appropriate (i.e. for the two treatment trials) and testing for trend using a likelihood ratio test. We tested the hypothesis that increased dose of drug leads to increased incidence of adverse effects.

Search methods for identification of studies

To identify trials in the manufacturer-funded clinical trial programmes for NIs, as well as non-manufacturer-funded clinical trials of NIs, we used a variety of methods applied to a variety of sources from the literature, manufacturers and from regulatory bodies. These methods, as well as our methodology for identifying and obtaining relevant clinical study reports, are detailed in Appendix 4, Appendix 5 and Appendix 6.

Electronic searches

We used electronic searches to identify trials not identified by the methods outlined in Appendix 4, particularly for non-manufacturer-funded clinical trials. See Appendix 5 for details. For the 2012 review, we updated our searches of the electronic databases of published studies that were previously carried out for the Cochrane reviews on NIs in children (Matheson 2007) and healthy adults (Jefferson 2010a), and then updated the searches again on 22 July 2013.

Searching other resources

For the description of our searches for regulatory information (FDA, EMA, Roche, GlaxoSmithKline (GSK), Japanese Pharmaceuticals and Medical Devices Agency (PMDA)), see Appendix 6.

Data collection and analysis

Collection and inventory of the evidence base was facilitated by the tools specifically developed for the review (Appendix 7). The overall risk of bias is presented graphically in Figure 1 and summarised in Figure 2.

Figure 1.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Other bias' includes potentially active placebos.

Figure 2.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
'Other bias' includes potentially active placebos.

Selection of studies

For this 2013 review, two authors (PD, TJ) reapplied the inclusion criteria for the oseltamivir clinical study reports and resolved disagreements by discussion. Two review authors (ES, IO) applied the criteria for the zanamivir clinical study reports while one review author (CH) arbitrated.

For the procedures followed in the 2012 review, see Appendix 8 and Appendix 9.

Data extraction and management

The sizeable quantity of available data led us to subdivide the extraction, appraisal and analysis of the data into a two-stage exercise. In Stage 1 we assessed the reliability and completeness of the identified trial data. We decided to include in Stage 2 of the review (full analysis following standard Cochrane methods) only data that satisfied the following three criteria.

  1. Completeness. Clinical study reports/unpublished reports include both identifiable CONSORT statement-specified methods to enable replication of the study. Identifiable CONSORT statement-specified results (primary outcomes, tables, appendices) must be available.

  2. Internal consistency. All parts (for example, denominators) of the same clinical study reports/unpublished report are broadly consistent.

  3. External consistency. Consistency of data as reported in regulatory documents, other versions of the same clinical study reports/unpublished reports and other references, to be established by cross-checking.

This was a different approach to that used in the previous version of the current review (Jefferson 2012), since we only had incomplete information at that time and only applied the second and third criteria.

Stage 1

For details of the use of the CONSORT-based extraction template and the assessment for Stage 1 inclusion in the A159 (Jefferson 2012) review, see Appendix 7. In this review assessment for inclusion in Stage 1 was part of the inclusion procedure.

Stage 2

In Stage 2, one review author extracted data and a second review author checked it. We extracted data onto standard forms, checked and recorded it.

Use of regulatory information

We used regulatory information to assess the possible correlation between citation frequency of oseltamivir treatment trials in the FDA regulatory documents and trial size.

Post-protocol analyses

After publication of the A159 protocol in December 2010, but before validation of our CONSORT-based extractions in the Northern Hemisphere spring of 2011, we decided to carry out analyses (which we called post-protocol analyses) to test five null hypotheses that we had formulated while reading, summarising and reconstructing the clinical study reports. The hypotheses originated from our observations of discrepancies and other unexpected observations in the clinical study reports' data and were informed by reading regulatory information. Appendix 10 reports the rationale, methods to formulate and test, and the results of the hypotheses.

The hypotheses reflect the uncertainty prevailing in the evidence base at a time when full clinical study reports were not available for all studies.

Assessment of risk of bias in included studies

Previous studies comparing regulatory with published or internal company sources of evidence have reported a variety of different biases that affect medical knowledge (Chou 2005; MacLean 2003; McGauran 2010; Wieseler 2013). We will report in detail elsewhere our comments on using the Cochrane 'Risk of bias' tool (Higgins 2011) to appraise clinical study reports and for trial programmes, and our efforts to construct an instrument for assessing risk of bias in complete clinical study reports. A full description of the methods used to quantify biases will be published in another paper.

Measures of treatment effect

To estimate treatment effects we first calculated the risk ratios (RRs) and used the average (mean) control event rate and the pooled RRs reported in the figures to calculate the risk differences (RD). For consistency we adopted this method for both the 'Summary of findings' tables and for the RDs reported in the text. For the analysis we chose to report the RRs as they are more consistent across the studies, and we have reported the heterogeneity for the pooled RR. We reinterpreted the results using the RD as this result is applicable to clinical decision-making. We calculated mean differences (MDs) for time to first alleviation of symptoms. For time to first alleviation of symptoms we also estimated the treatment effect as the percentage reduction in the average time to first alleviation of symptoms in the placebo group. Most zanamivir clinical study reports only reported treatment effects in terms of medians in each treatment group as well as P values from a hypothesis test comparing the time-to-event distributions. These data are insufficient for conducting meta-analysis. However, often sufficient time-to-event data were reported to allow us to estimate restricted means and standard deviations. Restricted means are based on the maximum time reported where alleviation occurred. There were some patients where alleviation was censored at the maximum follow-up time, therefore restricted means are under-estimates of the true means. However, the proportion of patients censored was generally low and similar in both treatment arms, hence this limitation is unlikely to have led to bias. The length of follow-up varied across trials and this has led to high variation in the estimated means and standard deviations (SDs) across trials.

A post hoc analysis was undertaken after we discovered seven zanamivir trials provided data on time to first alleviation of symptoms with and without relief medication. Each patient in the studies may or may not have taken relief medication during the trial. Alleviation of symptoms may have occurred while the patient was taking relief medication and the "standard" comparison was made using this scenario. However, an additional analysis used a stricter definition where alleviation of symptoms could only be achieved without the use of relief medication. For example, a patient may have achieved alleviation using relief medication after five days but took seven days to achieve alleviation without the use of relief medication. The comparison we reported is for all patients where we used the stricter definition for the zanamivir group (alleviation without relief medication) and the less strict definition for the placebo group (alleviation with relief medication).

We planned to use the tri-dimensional dose-relatedness, timing and patient susceptibility (DoTS) methodology to assess the likelihood of harms causality (Aronson 2003), but the quality of the data available did not allow for this.

Unit of analysis issues

Problems with unit of analysis are described in the 'Risk of bias' and 'Post-protocol hypotheses' sections.

Dealing with missing data

We developed a comprehensive strategy for dealing with data that we know are missing at the trial level, i.e. unpublished trials (see Search methods for identification of studies section and Appendix 4, Appendix 5 and Appendix 6) and unreliable published records, which are a very concentrated summary of clinical study reports. For example, in the oseltamivir trial programme, some trials' clinical study reports (e.g. WP16263) consist of 8545 pages. This has a 1000-fold greater length compared to its published version (Dutkowski 2010), which consists of seven pages. The purpose of this review is to provide as complete a picture as possible of trial programmes, without reliance on the published literature. Appendix 11 reports an example of the content of a typical Roche clinical study report.

Assessment of heterogeneity

We used Tau2 (inverse variance method) and the I2 statistic to estimate between-study variance as measures of the level of statistical heterogeneity and the Chi2 test to test for heterogeneity.

Assessment of reporting biases

We carried out assessment of reporting biases (comparing clinical study report with the relevant publication) only in the first publication of A159. For this version, as we had complete clinical study reports for the trial programmes of the two drugs, we expected to find all relevant information in these documents and adopted a binary assessment (high risk, low risk or unclear bias).

Data synthesis

We used the random-effects approach of DerSimonian and Laird based on MDs for analysis of time to first alleviation of symptoms. For all other outcomes we used the random-effects approach for binary data of DerSimonian and Laird, where Tau2 was estimated using the inverse variance method.

Whilst overall symptom reduction is well documented, our interest was particularly focused on complications and adverse events, as this is where evidence is currently scarce or inconclusive (Jefferson 2009a; Matheson 2007; Shun-Shin 2009). Our preliminary examination of clinical study reports identified that some symptoms and sequelae of influenza (such as “pneumonia”) had been classified as either a ‘complication of influenza’ or as an 'adverse event of the treatment’ or both. We called this somewhat confusing classification 'compliharms'. We decided to deal with compliharms as follows. We identified complications of particular clinical interest as “pneumonia”, bronchitis, otitis media and sinusitis. We tabulated the type of data capture used for each complication (“secondary illness”) by study including the following variables: definition of what events are termed complications, which part of the clinical study report captured data on complications, who reported and captured the data, which diagnostic method was used, whether and where the diagnostic pathway was (usually a form) and whether prescription for treatment were captured. We then aimed to stratify our analysis by method of diagnosis with three possible criteria: (1) laboratory-confirmed diagnosis (e.g. based on radiological- or microbiologically-confirmed evidence of infection); (2) clinical diagnosis without laboratory-confirmation (diagnosed by a doctor/investigator after a clinical examination); (3) other type of diagnosis such as self-reported by patient. We also conducted analysis of any complication (such as “pneumonia”, bronchitis, otitis media and sinusitis) that was classified as serious or led to study withdrawal.

We tested the effects of oseltamivir in prophylaxis of influenza and influenza-like illness. However the clinical study reports of prophylaxis trials do not define influenza-like illness but report eight different definitions for influenza with laboratory-confirmation (see web extra influenza definitions).

This is a complex and confusing set of definitions where, for example, the definition for Upper Respiratory Tract Infection (URTI) with systemic disturbance is the same as one of the definitions for asymptomatic influenza. After discovering the absence of a definition for influenza-like illness and the complex and confusing definitions for laboratory-confirmed influenza, we classified influenza-like illness as two or more symptoms from the following: nasal congestion, headache, chills/sweats, sore throat, cough, fatigue, myalgia and fever. These were the symptoms reported in the efficacy listing of individual patients in Module 3 of the prophylaxis trials clinical study reports.

In two oseltamivir treatment trials (WV15670; WV15671) and one prophylaxis study (WV15673/WV15697) there were three treatment arms comparing placebo, standard dose and high dose. For time to first alleviation of symptoms we restricted comparison to placebo versus standard dose (as this is how it was reported in the original report). However, for all other outcomes we combined the standard and high-dose treatment arms. There was little apparent difference in the incidence of outcomes between the standard and high-dose arms and combining the arms did not appear to cause heterogeneity. However, in two cases there was some evidence of a dose-response effect. These cases are described more fully in the Results section under 'Analysis of harms'.

The majority of zanamivir trials compared placebo with inhaled zanamivir. However, some trials also included an intranasal zanamivir treatment arm and a combined arm of inhaled and intranasal treatment. The multiple zanamivir arms were generally combined for meta-analysis as effects appeared similar and did not appear to cause heterogeneity.

Subgroup analysis and investigation of heterogeneity

We investigated the robustness of complications outcomes using subgroup analysis by method of diagnosis. We investigated high estimates of heterogeneity, where possible, using subgroup analysis. For example, we conducted subgroup analysis of time to first alleviation of symptoms in studies of oseltamivir treatment in children by partitioning studies into those of otherwise healthy children and those of children with chronic illness (asthma). Based on a referee's comment, we conducted a subgroup analysis on time to first alleviation of symptoms by infection status for zanamivir. We could not do a similar analysis for oseltamivir because we did not have data on the non-influenza-infected patients and we could not correctly identify the patients with influenza infection due to the effect of oseltamivir on antibodies.

In the trial programmes for both oseltamivir and zanamivir there was large variation in treatment effects for pneumonia across the populations studied (i.e. adults and children as well as treatment and prophylaxis), hence we conducted meta-regression to investigate this heterogeneity. We included all studies that reported pneumonia (32 studies in total) and investigated the four binary factors: age group (adults versus children); drug (oseltamivir versus zanamivir); indication (treatment versus prophylaxis) and method of diagnosis. For oseltamivir studies, the method of diagnosis was either based on data collected on non-specific adverse events or secondary/intercurrent illness forms or data collected on specific "diagnosis of secondary illness" forms that included objective criteria such as X-ray confirmation. For zanamivir, two trials included X-ray confirmation of pneumonia. We conducted meta-regression in Stata/SE, version 13 for Windows using the metareg command. There were some studies where one treatment group had zero events, therefore we added 0.5 events to all treatment groups for all studies prior to analysis. The dependent variable in the regression was log relative risk. A further post hoc analysis was undertaken after we discovered seven trials provided data on time to first alleviation of symptoms with and without relief medication. Each patient in the studies may or may not have taken relief medication during the trial. Alleviation of symptoms may have occurred while the patient was taking relief medication and the "standard" comparison was made using this scenario. However, an additional analysis used a stricter definition where alleviation of symptoms could only be achieved without the use of relief medication. For example, a patient may have achieved alleviation using relief medication after five days but took seven days to achieve alleviation without the use of relief medication. The comparison we reported is for all patients where we used the stricter definition for the zanamivir group (alleviation without relief medication) and the less strict definition for the placebo group (alleviation with relief medication).

Sensitivity analysis

Sensitivity analyses applicable to our post-protocol analyses have been covered earlier in the Methods section of this review. We used the fixed-effect method of Mantel and Haenszel as a sensitivity analysis to supplement our primary analyses using the random-effects method of DerSimonian and Laird. Random-effects meta-analysis is known to be overly conservative with sparse data. Hence we conducted sensitivity analysis using Peto's method on two occasions where we had sparse data and borderline statistically significant results (prophylaxis with oseltamivir: renal body system on-treatment and psychiatric body system on-treatment).

Results

Description of studies

We searched trial registries, electronic databases and regulatory archives, corresponded with manufacturers to identify all trials and requested clinical study reports. Although this review focuses on the primary data sources of manufacturers, we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 6), limited to year published 2010 to 2013 (20 search results); MEDLINE (January 2011 to July week 2, 2013) (56 search results) and MEDLINE (Ovid) from 1 January 2011 to July week 2, 2013 (56 search results); EMBASE (January 2011 to July 2013) (90 search results) and Embase.com from 1 January 2011 to July 2013 (90 search results); and PubMed (not MEDLINE) with no date limit (21 records). We searched PubMed to identify publisher-submitted records that will never be indexed in MEDLINE and the most recently added records not yet indexed in MEDLINE. To identify reviews that may possibly have referenced further trials we searched: the Database of Reviews of Effects (DARE) (2013, Issue 2 of 4 April) (four search results); the NHS Economic Evaluation Database (NHSEED) (Issue 2 of 4 April 2013) (two search results), both resources part of The Cochrane Library (accessed 22 July 2013), and the Health Economic Evaluations Database (HEED) (searched 22 July 2013) (three search results).

Results of the search

Use of regulatory information

We were able to download 2673 pages from the FDA website. The table of contents is in Table 2, Table 3, Table 4 and Table 5. We used these pages to identify all trials that had been conducted within a drug's trial programme. There was no correlation between citation frequency of oseltamivir treatment trials in the FDA regulatory documents and trial size. The biggest treatment trial (M76001) is cited only four times in three documents, while other contemporary treatment trials are cited far more (WV15670; WV15671; WV15730; WV15812/WV15872; WV15707). WV15670, for example, is cited 46 times in the FDA documents. However, the combined enrolled denominator of the four treatment trials completed at the time (WV15670; WV15671; WV15707; WV15730) was 1442, smaller than M76001 (1459). This suggested that the FDA's regulatory evaluation of Roche's New Drug Application was based predominantly on what Roche had offered them as "pivotal" or trials that best demonstrated the properties of oseltamivir, not the complete evidence base of all oseltamivir trials. One possible alternative explanation for this observation could have been the interval between trial completion, generation of the report and New Drug Applications (NDA) submission. This explanation is supported by the relatively brief interval between completion of the M76001 trial (19 February 1999) and submission (on 30 April 1999) of NDA 021087 to the FDA. However, the core part of the submission (the clinical development programme) contains data from two (at the time) ongoing trials (WV15819/WV15876/WV15978; WV15812/WV15872).

Table 2. Table of contents for studies of zanamivir described in regulatory documentation from the FDA (USA)
  1. Zanamivir trials citation by trial ID and source FDA file. Page numbers separated by commas (where applicable) indicate which trial is cited where in which regulatory file. Blank spaces indicate no citation for known trials.

    All the studies have been searched in the folder "Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036". File name is left blank when the study was not present in that folder.

Mentioned studyFile namePages where study is mentioned (separated by commas)Note
113502   
113625   
113678   
114045   
NAI108166   
105934   
NAI106784   
107485   
108127   
112311   
112312   
113268   
GCP/95/045   
NAI10901Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin2.pdf15.15 
NAI10902   
NAI30008Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin2.pdf157 documents with 14 instances
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin3.pdf13 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview7.pdf19, 19, 20 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview8.pdf1, 1, 3, 4, 4 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview9.pdf7.7 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/21036ltr.pdf2 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_MEDR.pdf33 
NAI30009Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview8.pdf1.27 documents with 110 instances
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_ADMINCORRES_P1.pdf 10, 10, 12, 13, 13, 14, 14, 17, 29, 42, 61, 62, 64, 64, 65, 65, 68 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_ADMINCORRES_P2.pdf 33, 34, 36, 43, 43, 43, 43, 52, 52, 52, 53, 53, 56, 57 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_BIOPHARMR.pdf5, 5, 5, 6, 6, 8, 8 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_MEDR.pdf3, 3, 3, 3, 3, 3, 3, 4, 4, 5, 8, 9, 9, 10, 10, 11, 11, 11, 14, 14, 15, 16, 17, 19, 19, 19, 20, 20, 22, 23, 23, 23, 24, 24, 24, 25, 25, 25, 25, 25, 25, 26, 26, 26, 27, 27, 28, 28, 28, 29, 29, 31, 31, 31, 31 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_MICROBR.pdf3, 3, 4, 4, 4 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_STATR.pdf2, 2, 2, 4, 7, 12, 18, 18, 18, 19 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_ADMINCORRES_P1.pdf31.561 document with 2 instances
NAI30010Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview8.pdf1.26 documents with 65 instances
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_ADMINCORRES_P1.pdf 10, 12, 13, 14, 14, 15, 17, 62, 62, 62, 64 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_ADMINCORRES_P2.pdf 34, 34, 36, 43, 53 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_BIOPHARMR.pdf5, 5, 6, 6 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_MEDR.pdf3, 3, 3, 3, 3, 4, 5, 18, 19, 21, 21, 22, 23, 23, 23, 23, 24, 25, 25, 25, 26, 26, 26, 26, 27, 27, 27, 28, 28, 29, 29, 29, 30, 31, 31, 31, 32 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_STATR.pdf2, 2, 13, 13, 13, 19 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_BIOPHARMR.pdf61 document with 1 instance
NAI30012Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview7.pdf11 document with 1 instance
NAI30015   
NAI30020   
NAI30028   
NAI30034   
NAI40012   
NAIA1009Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_ADMINCORRES_P1.pdf564 documents with 17 instances
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_ADMINCORRES_P2.pdf 1, 1, 1, 48, 49, 52 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_BIOPHARMR.pdf5, 5, 6 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_MEDR.pdf3, 3, 6, 7, 20, 31, 31 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview5.pdf185 documents with 5 instances
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview6.pdf9 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_ADMINCORRES_P2.pdf 52 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_BIOPHARMR.pdf11 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_STATR.pdf2 
NAIA3002Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin1.pdf1513 documents with 122 instances
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin2.pdf6, 6, 7, 7, 14, 15, 22, 22, 23 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin3.pdf1, 4, 4, 12, 12, 12, 12, 17 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview1.pdf4, 14, 14, 14, 14, 14, 15, 15, 15, 15, 16 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview2.pdf1, 2, 3, 4, 4, 5, 6, 6, 6, 8, 8, 9, 9, 9, 12, 12, 15, 16, 16, 16, 17 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview3.pdf5, 5, 6, 6, 6, 7, 7, 7, 8, 8, 9, 9, 9, 10, 11, 12, 13, 13, 14, 15, 15, 17, 18, 18, 19, 20, 21 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview4.pdf1, 1, 1, 1, 2, 6 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview6.pdf4, 5, 10, 12 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview7.pdf1, 1, 2, 2, 2, 2, 3, 3, 4, 4, 5, 5, 7, 8, 10, 11, 12, 14, 16, 16, 16, 16, 16, 17 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview8.pdf2, 2, 6, 6, 8, 8, 9, 10 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview9.pdf10 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-stats.pdf7 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_BIOPHARMR.pdf5 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview1.pdf151 document with 1 instance

NAIA3003

 

 

Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview7.pdf17, 17, 183 documents with 6 instances
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview8.pdf4.4 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview9.pdf22 
NAIA3004Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin3.pdf144 documents with 8 instances
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview6.pdf7 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview7.pdf18, 18, 19 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview8.pdf4, 4, 4 
NAIA3005Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin3.pdf145 documents with 12 instances
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview1.pdf5 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview5.pdf12, 12, 12, 13, 14, 15, 15 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview7.pdf14.15 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_ADMINCORRES_P2.pdf 38 
NAIB1002   
NAIB3002Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin1.pdf1514 documents with 99 instances
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin2.pdf14, 15, 15, 15 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin3.pdf11.12 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview1.pdf4, 14, 14, 14, 14, 14, 14, 14, 14 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview2.pdf9, 9, 9, 9, 9, 9, 10, 11, 12, 12, 12, 12, 13, 13, 13, 14, 14, 14, 15, 15, 16, 16, 16, 17 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview3.pdf4, 5, 6, 6, 6, 7, 7, 7, 8, 8, 8, 9, 9, 11, 12, 12, 13, 13, 14, 15, 17, 18, 18, 19, 20, 21 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview4.pdf1, 1, 1, 1, 2 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview5.pdf4 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview6.pdf4, 5, 10, 12 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview7.pdf2, 3, 3, 7, 8, 10, 11, 14, 15, 16, 16, 16 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview8.pdf7, 8, 8, 8, 9, 9 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview9.pdf10.2 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-stats.pdf7 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_BIOPHARMR.pdf5.5 
NAI30011   
NAIB2007Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin1.pdf157 documents with 18 instances
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin2.pdf15 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview1.pdf5 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview4.pdf14, 15, 15, 16, 16, 17, 17, 17, 18 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview6.pdf3 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview7.pdf8, 10, 10, 15 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview8.pdf2 
NAIA2006   
NAIB2006   
NAIB1007   
C94-009Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview5.pdf171 document with 1 instance

C94-085

 

Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview5.pdf172 documents with 2 instances
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview9.pdf22 
NAIB1001Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_BIOPHARMR.pdf171 document with 1 instance
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/20000426_001/21-036-S001_RELENZA_BIOPHARMR.pdf61 document with 1 instance
NAIA2005Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin1.pdf1510 documents with 44 instances
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin2.pdf7, 17, 10 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin3.pdf2.4 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview1.pdf4.5 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview4.pdf2, 2, 3, 3, 3, 3, 5, 6, 6, 6, 6, 8, 8, 8, 9, 11, 12, 12, 13, 14, 14, 14, 14, 14, 15, 18 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview5.pdf7.7 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview6.pdf3.4 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview7.pdf2, 5, 9, 15 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview8.pdf10 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-microbiology.pdf21 
NAIB2005Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin1.pdf159 documents with 43 instances
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-admin2.pdf17, 20, 20, 22, 23 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview1.pdf5.5 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview4.pdf3, 3, 3, 7, 8, 8, 8, 9, 10, 11, 11, 11, 11, 11, 12, 12, 12, 13, 14, 14, 14, 14, 14, 14, 14, 15 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview5.pdf7.7 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview6.pdf3.4 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview7.pdf2, 9, 15 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview8.pdf2 
Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-microbiology.pdf21 
NAIA/B2008Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview6.pdf41 document with 1 instance
NAIA2010Tamiflu and Relenza/Relenza/Relenza - NDA 021036/19990726_000/021036-medreview5.pdf161 document with 1 instance
NAIA/B2009   
167-02   
167-03   
167-05   
167-04   
JNAI-03   
JNAI-02   
JNAI-01   
JNAI-07   
JNAI-04   
PE-01   
167-101   
167T3-11    
Table 3. Table of contents for studies of oseltamivir described in regulatory documentation from the FDA (USA)
  1. Oseltamivir trials citation by trial ID and source FDA file. Page numbers separated by commas (where applicable) indicate which trial is cited where in which regulatory file. Blank spaces indicate no citation for known trials.

    Search strategy:
    WV15758 OR WV 15758 OR Trial 15758 OR Trial15758 OR Trials 15758 OR Trials15758 OR 15758 OR study 15758 OR study15758

Referenced studyFile namePages where study is mentioned (separated by commas)Note
NP15717Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_bior.pdf46.466 documents with 13 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf14, 15, 15 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20040624_010/021087_S016_TAMIFLU CAPSULES - DRY POWDER_BIOPHARMR.pdf3 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Admindocs_P2.pdf2 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_BioPharmr.pdf5, 8, 10, 13, 31 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20040624_010/021087_S016_TAMIFLU CAPSULES - DRY POWDER_BIOPHARMR.pdf3 
NP15718Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_bior.pdf171 document with 1 instance
NP15728 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_bior.pdf16.353 documents with 6 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P1.pdf11 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf45, 46, 47 
NP15757Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20001117_002/21-087SE1-002_review.pdf92, 93, 104, 122, 126, 131, 144, 144, 1451 document with 9 instances
NP15826 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf479 documents with 26 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20040624_016/021087_S016_TAMIFLU CAPSULES - DRY POWDER_ADMINCORRES.pdf6 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20040624_010/021087_S016_TAMIFLU CAPSULES - DRY POWDER_BIOPHARMR.pdf3 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Admindocs_P2.pdf2 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_BioPharmr.pdf4, 5, 5, 8, 8, 8, 10, 17, 29, 30, 30, 30, 30, 30, 31, 31 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Medr.pdf9.1 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Statr.pdf9.1 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20040624_016/021087_S016_TAMIFLU CAPSULES - DRY POWDER_ADMINCORRES.pdf6 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20040624_010/021087_S016_TAMIFLU CAPSULES - DRY POWDER_BIOPHARMR.pdf3 
NP15827 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P1.pdf10.122 documents with 7 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf16, 16, 17, 17, 17 
WP15525 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_bior.pdf21, 25, 26, 27, 27, 27, 27, 42, 42, 443 document with 13 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Admindocs_P2.pdf2.2 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_BioPharmr.pdf29 
WP15647Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_bior.pdf24, 27, 272 documents with 4 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf44 
WP15648 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_bior.pdf393 documents with 8 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf44.44 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20001117_002/21-087SE1-002_review.pdf94, 128, 153, 153, 154 
WP15676 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_bior.pdf28.333 documents with 4 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P1.pdf11 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf45 
WV15670 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_bior.pdf2, 44, 446 documents with 45 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P1.pdf6, 19, 37, 38, 39, 39, 39, 39, 40, 41, 41, 42, 43, 44, 48, 48, 49, 49 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf1, 25, 25, 35, 35, 39, 39, 47 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Statr.pdf3, 3, 4, 4, 5, 5, 5, 8, 9, 10, 17, 17, 21, 22, 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20001117_002/21-087SE1-002_review.pdf189 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20040624_010/021087_S016_TAMIFLU CAPSULES - DRY POWDER_BIOPHARMR.pdf3 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20040624_010/021087_S016_TAMIFLU CAPSULES - DRY POWDER_BIOPHARMR.pdf3 
WV15671 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_bior.pdf2, 44, 447 documents with 50 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P1.pdf6, 16, 19, 24, 24, 25, 25, 26, 27, 27, 28, 32, 34, 35, 36, 37, 38, 39, 39, 39, 40, 41, 46, 49, 49 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf1, 25, 25, 35, 38, 47 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Statr.pdf3, 4, 4, 5, 5, 5, 5, 9, 10, 10, 15, 17, 21 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20001117_002/21-087SE1-002_review.pdf189 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20040624_010/021087_S016_TAMIFLU CAPSULES - DRY POWDER_BIOPHARMR.pdf3 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20040624_010/021087_S016_TAMIFLU CAPSULES - DRY POWDER_BIOPHARMR.pdf3 
WV15673 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P1.pdf33 documents with 50 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf18, 18, 18, 20, 21, 21, 21, 22, 39 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20001117_002/21-087SE1-002_review.pdf58, 59, 71, 71, 71, 71, 71, 72, 72, 73, 73, 76, 76, 76, 76, 76, 77, 77, 79, 82, 83, 83, 84, 122, 124, 125, 126, 128, 131, 131, 132, 133, 134, 134, 145, 145, 156, 169, 177, 189 
WV15697 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf392 documents with 40 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20001117_002/21-087SE1-002_review.pdf58, 59, 71, 71, 71, 71, 71, 72, 72, 73, 73, 76, 76, 76, 76, 76, 77, 77, 79, 82, 83, 83, 84, 122, 126, 128, 131, 131, 131, 132, 133, 134, 145, 145, 152, 153, 156, 162, 189 
WV15708 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P1.pdf33 documents with 39 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf23, 35, 39, 41 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20001117_002/21-087SE1-002_review.pdf71, 71, 71, 71, 71, 72, 72, 72, 72, 75, 75, 75, 75, 77, 77, 78, 79, 79, 82, 82, 122, 125, 125, 126, 131, 134, 134, 135, 135, 149, 151, 152, 152, 153 
WV15708D Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P1.pdf32 documents with 3 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf23.35 
WV15730 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_bior.pdf44.445 documents with 15 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P1.pdf6, 9, 19, 49, 50, 50 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf1, 1, 25, 25, 27 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20001117_002/21-087SE1-002_review.pdf189 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20040624_010/021087_S016_TAMIFLU CAPSULES - DRY POWDER_BIOPHARMR.pdf3 
WV15731 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Admindocs_P2.pdf174 documents with 9 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Medr.pdf5, 30, 37 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Microbr.pdf5.6 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Statr.pdf5, 30, 37 
WV15758 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Admindocs_P1.pdf12, 19, 19, 369 documents with 92 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Admindocs_P2.pdf2, 8, 17, 39, 39, 57, 57 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_BioPharmr.pdf3, 4, 5, 5, 5, 8, 10, 17, 27, 30 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Corres.pdf6.9 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Medr.pdf5, 5, 9, 9, 10, 11, 12, 12, 16, 18, 18, 18, 19, 19, 31, 31, 31, 33, 33, 35, 36, 37, 37, 37, 37, 37, 37, 37, 40, 43 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Microbr.pdf2, 4, 5, 6 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Statr.pdf5, 5, 9, 9, 10, 11, 12, 12, 16, 18, 18, 18, 19, 19, 31, 31, 31, 33, 33, 35, 36, 37, 37, 37, 37, 37, 37, 37, 40, 43 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20040624_016/021087_S016_TAMIFLU CAPSULES - DRY POWDER_ADMINCORRES.pdf6, 6, 8 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20040624_010/021087_S016_TAMIFLU CAPSULES - DRY POWDER_BIOPHARMR.pdf2.3 
WV15759 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Admindocs_P1.pdf12.137 documents with 44 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Admindocs_P2.pdf39 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Medr.pdf5, 10, 30, 30, 30, 30, 31, 32, 32, 33, 34, 37, 37, 37, 40, 44 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Microbr.pdf2, 4, 4, 5, 6 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Statr.pdf5, 10, 30, 30, 30, 30, 31, 32, 32, 33, 34, 37, 37, 37, 40, 44 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20040624_016/021087_S016_TAMIFLU CAPSULES - DRY POWDER_ADMINCORRES.pdf6, 6, 9 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20040624_010/021087_S016_TAMIFLU CAPSULES - DRY POWDER_BIOPHARMR.pdf2 
WV15799 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20001117_002/21-087SE1-002_review.pdf28, 28, 28, 28, 28, 29, 29, 30, 30, 30, 30, 30, 31, 31, 31, 31, 32, 32, 32, 32, 32, 33, 33, 34, 34, 35, 35, 35, 36, 37, 37, 37, 37, 37, 38, 38, 38, 39, 39, 40, 40, 40, 40, 40, 58, 60, 71, 71, 71, 71, 71, 72, 72, 73, 76, 76, 76, 77, 78, 79, 84, 85, 122, 125, 125, 126, 126, 128, 131, 140, 140, 140, 143, 147, 149, 156, 162, 169, 175, 187, 203, 208, 2084 documents with 89 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Medr.pdf10.11 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Statr.pdf10.11 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20040624_016/021087_S016_TAMIFLU CAPSULES - DRY POWDER_ADMINCORRES.pdf6.7 
WV15812 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P1.pdf3, 6, 10, 122 documents with 9 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf6, 8, 10, 25, 35 
WV15819 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P1.pdf6, 10, 12, 152 documents with 8 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/19991027_000/21087_Tamiflu_medr_P2.pdf2, 6, 6, 39 
WV15825 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20001117_002/21-087SE1-002_review.pdf41, 41, 41, 41, 42, 42, 42, 42, 42, 42, 43, 44, 58, 59, 71, 71, 71, 71, 71, 72, 72, 72, 72, 73, 73, 75, 75, 77, 77, 78, 79, 79, 79, 80, 80, 80, 81, 82, 85, 125, 125, 126, 126, 128, 131, 134, 134, 135, 135, 137, 137, 138, 145, 150, 151, 152, 152, 155, 156, 162, 169, 180, 204, 2111 document with 64 instances
WV15871 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Admindocs_P1.pdf12.137 documents with 42 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Admindocs_P2.pdf39 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Medr.pdf5, 11, 30, 31, 31, 32, 32, 32, 33, 34, 37, 37, 37, 37, 37, 37, 40 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Microbr.pdf2, 5, 6 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Statr.pdf5, 11, 30, 31, 31, 32, 32, 32, 33, 34, 37, 37, 37, 37, 37, 37, 40 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021087/20040624_016/021087_S016_TAMIFLU CAPSULES - DRY POWDER_ADMINCORRES.pdf6 
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20040624_010/021087_S016_TAMIFLU CAPSULES - DRY POWDER_BIOPHARMR.pdf2 
WV15872 Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Medr.pdf11.332 documents with 4 instances
Tamiflu and Relenza/Tamiflu/Tamiflu - NDA 021246/20001214_000/21-246_Tamiflu_Statr.pdf11.33 
Table 4. Table of contents for studies of zanamivir described in regulatory documentation from NICE (UK)
  1. Zanamivir trials citation by trial ID and source NICE file. Page numbers separated by commas (where applicable) indicate which trial is cited where in which file. Blank spaces indicate no citation for known trials

Mentioned studyFile namePages where study is mentioned (separated by commas)Note
NAI106784   
107485   
108127   
112311   
112312   
113268   
GCP/95/045   
NAI10901   
NAI10902   
NAI30008Relenza treatment submission executive summary.pdf43 documents with 10 instances
Relenza treatment submission full document.pdf5, 26, 26, 26, 146 
Relenza treatment submission main text.pdf5, 26, 26, 26 
NAI30009NAI30010 study report pdf\FINAL NAI30010 for sign-off.pdf1027 documents with 461 instances
NAI30009 study report pdf\CSR30009.pdf  
NAI30009 study report pdf\NAI 30009 HO final FSR.pdf  
NAI30009 study report pdf\suptables.pdf  
NAI30009 study report pdf\tables.pdf  
Relenza treatment submission full document.pdf16, 16, 17, 18, 18, 18, 18, 19, 27, 30, 31, 
Relenza treatment submission main text.pdf16, 16, 17, 18, 18, 18, 18, 19, 27, 30, 31, 76, 128, 130, 132, 134, 144 
NAI30010NAI30010 study report\Final NAI30010 for sign-off.pdf 7 documents with 399 instances
NAI30010 study report pdf\NAI30010 HO final FSR.pdf  
NAI30010 study report pdf\suptables.pdf  
NAI30010 study report pdf\tables.pdf  
Relenza prophylaxis submission.pdf2, 5, 8, 11, 12, 19, 20, 21, 23, 24 
Relenza treatment submission full document.pdf16, 16, 17, 18, 18, 18, 27, 30, 31, 76, 135, 137, 139, 141, 143, 144 
Relenza treatment submission main text.pdf16, 16, 17, 18, 18, 18, 27, 30, 31 
NAI30012Relenza treatment submission executive summary.pdf43 documents with 8 instances
NAI30012Relenza treatment submission full document.pdf5, 26, 26, 146 
NAI30012Relenza treatment submission main text.pdf5, 26, 26 
NAI30015Relenza treatment submission full document.pdf1461 document with 1 instance
NAI30020   
NAI30028   
NAI30031   
NAI30034   
NAI40012   

NAIA1009

 

NAI30010 study report pdf\FINAL NAI30010 for sign-off.pdf1012 documents with 3 instances
NAI30009 study report pdf\CSR30009.pdf28.34 

NAIA3002

 

 

 

 

 

 

 

 

NAI30010 study report pdf\FINAL NAI30010 for sign-off.pdf1029 documents with 513 instances
NAI30009 study report pdf\CSR30009.pdf34.95 
NAI30009 study report pdf\NAI30009 HO final FSR.pdf22 
NAIA3002 study report pdf\NAIA3002 full study report.pdf  
NAIA3002 study report pdf\NAIA3002 supporting tables 2.pdf  
NAIA3005 study report pdf\A3005cr01.pdf25 
NAIB3002 study report pdf\NAIB3002 full study report.pdf28, 47, 49 
Relenza treatment submission full document.pdf16, 16, 17, 17, 18, 19, 27, 30, 31, 63, 63, 63, 76, 106, 106, 107, 107, 109, 109, 112, 112, 114, 114, 115, 115, 144 
Relenza treatment submission main text.pdf16, 16, 17, 17, 18, 19, 27, 30, 31 
NAIA3003Relenza prophylaxis submission.pdf101 document with 1 instance
NAIA3004Relenza prophylaxis submission.pdf101 document with 1 instance
NAIA3005NAI30010 study report pdf\FINAL NAI30010 for sign-off.pdf36, 94, 94, 94, 95, 96, 96, 1015 documents with 310 instances
NAI30010 study report pdf\NAI30010 HO FSR.pdf6.18 
NAIA3005 study report pdf\A3005cr01.pdf  
NAIA3005 study report pdf\TABS.pdf  
Relenza prophylaxis submission.pdf2, 5, 6, 12, 13, 13, 15, 15, 16, 16, 17, 17, 18, 18 
NAIB1002   
NAIB3001NAI30009 study report pdf\CSR30009.pdf34, 50, 9511 documents with 374 instances
NAI30009 study report pdf\NAI 30009 HO final FSR.pdf10.22 
NAI30010 study report pdf\FINAL NAI30010 for sign-off.pdf102 
NAI30010 study report pdf \NAI30010 HO FSR.pdf17.17 
NAIA3002 study report pdf\NAIA3002 full study report.pdf28 
NAIA3005 study report pdf\A3005cr01.pdf25 
NAIB3001 study report pdf\NAIB3001 full study report.pdf  
NAIB3001 study report pdf\NAIB3001 supporting tables 1.pdf  
NAIB3002 study report pdf\NAIB3002 full study report.pdf28 
Relenza treatment submission full document.pdf16, 16, 17, 18, 18, 18, 18, 27, 30, 31, 32, 63, 63, 63, 76, 99, 99, 101, 101, 103, 103, 105, 105, 144, 162 
Relenza treatment submission main text.pdf16, 16, 17, 18, 18, 18, 18, 27, 30, 31, 32 
NAIB3002NAI30009 study report pdf\CSR30009.pdf34.9510 documents with 579 instances
NAI30009 study report pdf\NAI 30009 HO final FSR.pdf22 
NAI30010 study report pdf\FINAL NAI30010 for sign-off.pdf102 
NAIA3002 study report pdf\NAIA3002 full study report.pdf28, 48, 50 
NAIA3005 study report pdf\A3005cr01.pdf25 
NAIB3002 study report pdf\NAIB3002 full study report.pdf  
NAIB3002 study report pdf\NAIB3002supporting tables 1.pdf  
NAIB3002 study report pdf\NAIB3002supporting tables 2.pdf  
Relenza treatment submission full document.pdf16, 16, 17, 17, 18, 19, 27, 30, 31, 63, 63, 63, 76, 117, 117, 117, 118, 118, 120, 120, 122, 122, 124, 124, 125, 125, 127, 127, 144 
Relenza treatment submission main text.pdf16, 16, 17, 17, 18, 19, 27, 30, 31 
NAI30011Relenza treatment submission full document.pdf1461 document with 1 instance
NAIB2007NAI30009 study report pdf\CSR30009.pdf9510 documents with 379 instances
NAI30009 study report pdf\NAI 30009 HO final FSR.pdf10 
NAIA3002 study report pdf\NAIA3002 full study report.pdf28, 28, 29 
NAIA3005 study report pdf\A3005cr01.pdf25 
NAIB2007 study report pdf\b2007cr.pdf  
NAIB2007 study report pdf\TABLES.pdf  
NAIB3001 study report pdf\NAIB3001 full study report.pdf25.26 
NAIB3002 study report pdf\NAIB3002 full study report.pdf28, 28, 29 
Relenza treatment submission full document.pdf16, 16, 17, 18, 18, 19, 27, 30, 31, 76, 91, 91, 92, 92, 94, 94, 96, 96, 98, 98, 144 
Relenza treatment submission main text.pdf16, 16, 17, 18, 18, 19, 27, 30, 31 
NAIA2006NAIA2005 study report pdf\a2005cr.pdf38, 73, 744 documents with 6 instances
NAIA3002 study report pdf\NAIA3002 full study report.pdf28 
NAIA3005 study report pdf\A3005cr01.pdf25 
NAIB3002 study report pdf\NAIB3002 full study report.pdf28 
NAIB2006NAIA3002 study report pdf\NAIA3002 full study report.pdf283 documents with 3 instances
NAIA3005 study report pdf\A3005cr01.pdf25 
NAIB3002 study report pdf\NAIB3002 full study report.pdf28 
NAIB1007   
C94-009   
C94-085   
NAIB1001   
NAIB_1001   

NAIA2005

 

 

 

 

 

 

 

 

 

 

 

NAI30009 study report pdf\CSR30009.pdf9512 documents with 895 instances
NAIA2005 study report pdf\a2005cr.pdf  
NAIA2005 study report pdf\APPS_ALL.pdf  
NAIA2005 study report pdf\TBS_ALL.pdf  
NAIA3002 study report pdf\NAIA3002 full study report.pdf28, 28, 48, 48 
NAIA3005 study report pdf\A3005cr01.pdf25 
NAIB2005 study report pdf\b2005cr.pdf7, 7, 22, 25, 26, 34, 34, 42, 71, 72, 72 
NAIB2007 study report pdf\b2007cr.pdf76 
NAIB3001 study report pdf\NAIB3001 full study report.pdf25 
NAIB3002 study report pdf\NAIB3002 full study report.pdf28, 28, 47, 47 
Relenza treatment submission full document.pdf16, 16, 16, 16, 17, 18, 27, 30, 76, 77, 77, 77, 79, 79, 79, 80, 80, 82, 82, 84, 84, 85, 144, 144 
Relenza treatment submission main text.pdf16, 16, 16, 16, 17, 18, 27, 30 

NAIB2005

 

 

 

 

 

 

 

 

 

 

 

NAI30009 study report pdf\CSR30009.pdf9512 documents with 838 instances
NAIA2005 study report pdf\a2005cr.pdf7, 8, 8, 24, 24, 25, 43, 70, 74, 74 
NAIA3002 study report pdf\NAIA3002 full study report.pdf28, 28, 48, 48 
NAIA3005 study report pdf\A3005cr01.pdf25 
NAIB2005 study report pdf\APPSNEW.pdf  
NAIB2005 study report pdf\b2005cr.pdf  
NAIB2005 study report pdf\TBS_ALL.pdf  
NAIB2007 study report pdf\b2007cr.pdf76 
NAIB3001 study report pdf\NAIB3001 full study report.pdf25 
NAIB3002 study report pdf\NAIB3002 full study report.pdf28, 28, 47, 47 
Relenza treatment submission full document.pdf16, 16, 16, 16, 17, 18, 27, 30, 76, 77, 79, 79, 85, 85, 85, 86, 86, 88, 88, 90, 90, 144, 144 
Relenza treatment submission main text.pdf16, 16, 16, 16, 17, 18, 27, 30 

NAIA/B2008

 

 

 

 

 

NAI30009 study report pdf\CSR30009.pdf956 documents with 16 instances
NAI30009 study report pdf\NAI 30009 HO final FSR.pdf10 
NAIA3002 study report pdf\NAIA3002 full study report.pdf28, 28, 29, 29 
NAIA3005 study report pdf\A3005cr01.pdf25 
NAIB3001 study report pdf\NAIB3001 full study report.pdf25, 26, 26, 26, 77 
NAIB3002 study report pdf\NAIB3002 full study report.pdf28, 28, 29, 29 
NAIA2010NAIA3005 study report pdf\A3005cr01.pdf251 document with 1 instance
NAIA/B2009NAIA3002 study report pdf\NAIA3002 full study report.pdf283 documents with 3 instances
NAIA3005 study report pdf\A3005cr01.pdf25 
NAIB3002 study report pdf\NAIB3002 full study report.pdf28 
167-02   
167-03   
167-05   
167-04   
JNAI-03   
JNAI-02   
JNAI-01   
JNAI-07   
JNAI-04   
PE-01   
167-101   
167T3-11    
Table 5. Table of contents for studies of oseltamivir described in regulatory documentation from NICE (UK)
  1. Oseltamivir trials citation by trial ID and source NICE file. Page numbers separated by commas (where applicable) indicate which trial is cited where in which file. Blank spaces indicate no citation for known trials.

    All the studies have been searched in the folder "Roche submission".

    When there is the number of the volume but no pages are mentioned, it means that the code of the study is cited more than 100 times.

    *Number of the volume of the Tamiflu NICE submission.

Referenced studyFile name volume*Pages where study is mentioned (separated by commas)Note
133312   
GS97-802   
133312   
GS-97-801   
JP15734   
JP15735   
JV15823   
JV15824   
JV16284   
M76001133, 36, 37, 37, 38, 38, 39, 67, 68, 94, 95, 2241 document with 12 instances
M76006   
ML20910   
ML22789   
ML22879   
MV21118   
MV22841   
NCT00298233   
NCT00555893   
NCT00707941   
NCT00799760   
NCT00830323   
ML25018   
NCT00867139   
NCT00873886   
NCT01002729   
NP15717632, 75, 76, 772 documents with 5 instances
868 
673.981 document with 2 instances
NP15718   
NP15728   
NP157578681 document with 1 instance
NP15826632, 75, 75, 75, 76, 76, 77, 78, 79, 80, 981 document with 11 instances
NP158278681 document with 1 instance
NP22770   
NP25138   
NP25139   
NV16871   
NV20234   
NV20235    
NV20236   
NV20237   
NV22155   
NV25118   
NV25182   
PP16351   
WP155171185.2451 document with 2 instances
WP155251185.2451 document with 2 instances
WP15647   
WP15648   
WP15676   
WP15901   
WP22849   
WV144181   
WV15670133, 36, 37, 37, 38, 38, 39, 47, 48, 48, 49, 49, 50, 53, 54, 54, 55, 163, 171, 188, 207, 209, 224, 245, 245, 252, 253, 2537 documents with 1193 instances
107, 36, 37, 37 
2  
3  
490 
635.98 
865 
220, 20, 20, 20, 201 document with 5 instances

WV15671

 

133, 36, 37, 37, 38, 38, 39, 47, 48, 49, 49, 50, 53, 54, 54, 55, 163, 171, 188, 207, 209, 224, 245, 2457 documents with 1222 instances
107, 36, 37, 37 
282 
4  
5  
635.98 
866 
WV156738661 document with 1 instance
WV15673D8661 document with 1 instance
WV156978 1 document with 1 instance
WV15697D8 1 document with 1 instance
WV15707133, 36, 37, 37, 38, 67, 68, 224, 245, 245, 245, 2461 document with 12 instances
WV15708   
WV15708D   
WV15730133, 36, 37, 37, 38, 38, 39, 47, 53, 54, 55, 186, 207, 224, 245, 245, 2464 documents with 22 instances
107, 36, 37 
282 
490 
WV157316981 document with 1 instance
WV15758136, 37, 82, 83, 84, 85, 86, 92, 94, 95, 97, 106, 224, 2464 documents with 424 instances
6  
7  
868 
WV15759136, 37, 94, 95, 95, 109, 113, 114, 121, 122, 224, 2461 document with 12 instances
WV157991137, 139, 139, 232, 2333 documents with 499 instances
8  
9  
WV15812136, 37, 37, 38, 38, 39, 67, 68, 68, 107, 107, 107, 108, 108, 121, 121, 122, 123, 224, 2462 documents with 197 instances
10  
WV15819133, 36, 37, 37, 38, 58, 58, 59, 59, 60, 61, 62, 62, 65, 65, 67, 68, 224, 2462 documents with 173 instances
10  
WV15825866, 661 document with 2 instances
WV158711109, 2461 document with 2 instances
WV15872136, 37, 37, 38, 38, 39, 67, 68, 68, 107, 107, 108, 108, 121, 121, 122, 123, 2241 document with 18 instances
WV158761246, 2461 document with 2 instances
WV15978167, 70, 175, 246, 2461 document with 5 instances
WV16193   
ML16369   

The basis of the selection of trials to regulators is therefore unclear but appears to be dictated by criteria other than availability and size. The importance of trials (to manufacturers and possibly to regulators) may not be based on the same criteria that systematic reviewers would use (i.e. the capability of the trial to answer questions).

Due to the vast size of FDA documents, sometimes hundreds of pages long, it was difficult to determine important emerging themes solely by reading. To identify items of interest in the FDA comments we used word clouds (Feinberg 2009). Word clouds give greater prominence to words that appear more frequently in the source document. The resulting graphic representation showed words such as 'diary' and 'baseline' to be heavily mentioned in the relevant (abridged) text from the FDA's Medical Officer Review (FDA 1999c, PDF page 19). Examining the 'diary' entry in more detail, we found the following FDA comment:

"The majority of subjects participating in the treatment trials had only used the first diary card. The second diary card was issued in 15% to 20% of participants. In response to FDA's request, the applicant provided a summary of diary card dispensing in the 8/6/99 submission. It became apparent that instructions on when to start a second diary card were not uniformly followed in WV15670, WV15671, and WV15730 trials. There were examples of patients who had alleviated symptoms yet also received a second diary card. Conversely, there were also examples of patients who did not alleviate all symptoms but did not receive a second diary card. Thus the second diary card was used inconsistently which is viewed as a flaw of these trials. The lack of consistency in collecting symptom information after alleviation precluded a complete documentation of symptom fluctuation. Also missing second diary cards in subjects who had not alleviated symptoms were responsible for the majority of censored data which may have potentially influenced the results of efficacy analysis. In order to address the impact of censoring, the applicant performed several sensitivity analyses which will be summarized in the Integrated Summary of Efficacy".

This comment highlights problems with the follow-up procedure of treatments trials, which may have impaired the regulator's ability to draw conclusions on the duration of effect of oseltamivir. It also provides a good example of how graphic methods can help identify crucial comments in vast regulatory files.

Several other experiments with text from the same FDA document showed that the choice of text to be represented as a Word cloud heavily influenced cloud construction, visibility of words and hence our ability to detect important comments. It is for this reason that we decided to adopt a mixed approach: mapping citations while reading FDA comments and integrating such comments in our appraisal of the evidence. Regulatory comments were all the more important, because at the time we developed this method we had few clinical study reports and comments helped to identify the gaps in our knowledge of the trial programmes.

Once the table of contents had been constructed, we postulated that given the huge work involved in reviewing lots of regulatory files, our new instrument could also help us by indicating which parts were more important than others, thus focusing our efforts. We experimented with a variety of methods reported in the Data collection and analysis section.

Clinical study reports

After prolonged correspondence and media pressure (Appendix 2), we were able to access the trial programmes for both oseltamivir and zanamivir without clauses restricting their accessibility to third parties.

Electronic searches

Two review authors (CDM, MT) independently scanned the titles and abstracts of the electronic searches. Three identified studies (NCT00980109; NCT01032837; JPRN-JapicCTI-111647) were published versions of trials possibly unknown to us. We wrote to the first trial author to ask for clinical study reports or equivalent on 12 November 2013 who confirmed that the trials had not been completed.

Included studies

The absence of documentation of trial programmes for both drugs, listing all sponsored trials completed or underway, meant we had to rely on a variety of sources for the reconstruction of the trial programmes and identification of relevant clinical study reports. This complexity is reflected in the flowchart presented in Figure 3, illustrating the study selection process for this review. The two main pathways were the spontaneous release of 77 full clinical study reports by Roche (long after our request for 36 of them) and the requests to regulatory authorities and GSK for all the relevant reports.

Figure 3.

Flow diagram describing the number of studies identified, inclusion, exclusion and progression from identification to stage 1 to stage 2 of the review.

NB Because of the absence of trial programmes for both drugs listing all sponsored trials completed or underway, we had to rely on a variety of sources for the reconstruction of the trial programmes and retrieval of relevant clinical study reports. This complexity is reflected in the flowchart, illustrating the study selection process for this review. The two main pathways were the spontaneous release of 77 clinical full clinical study reports by Roche and the requests to regulatory authorities and GSK for all the relevant reports. There was overlap in trial reports retrieved following the different pathways

We carried out the inclusion into Stage 1 using the clinical study reports, titles, abstracts and any other relevant information. Through this process we identified 208 potentially relevant studies (139 oseltamivir trials, 61 zanamivir trials and eight peramivir trials). We excluded 123 studies (listed in the Characteristics of excluded studies table) as clearly ineligible. A further 19 studies are awaiting classification (see Characteristics of studies awaiting classification). We requested 66 trials from study sponsors, the EMA and the FDA. From these different methods the total number of trials available for assessment for inclusion in our review at Stage 1 was 53.

Twenty three studies of oseltamivir (JV15823; JV15824; M76001; ML16369; NV16871; WV15670; WV15671; WV15673/WV15697; WV15707; WV15708; WV15730; WV15758; WV15759/WV15871; WV15799; WV15812/WV15872; WV15819/WV15876/WV15978; WV15825; WV16277) and 28 of zanamivir (167-101; JNAI-01; JNAI-04; JNAI-07; NAI30008; NAI30009; NAI30010; NAI30011; NAI30012; NAI30015; NAI30020; NAI30028; NAI30031; NAI30034; NAIA/B2008; NAIA/B2009; NAIA2005; NAIA2006; NAIA3002; NAIA3003; NAIA3004; NAIA3005; NAIB2005; NAIB2006; NAIB2007; NAIB3001; NAIB3002; PE-01) were included in Stage 1. It was not uncommon for more than one trial to be reported in the same clinical study reports. This was either due to the amalgamation of two or more trials because of low influenza virus circulation and difficulties in recruitment (for example, WV15812/WV15872), or because the trials bore different ID numbers when in reality they followed the same protocol, albeit in two different hemispheres (for example, WV15759/WV15871).

We also identified six completed or ongoing studies of peramivir in dose-response or placebo-controlled studies (NCT00419263; NCT00453999; NCT00486980; NCT00610935; NCT00705406; NCT00958776).

The included trials were predominantly conducted in adults during influenza seasons in both hemispheres. A small number of studies were conducted in older people residing in care homes and in people with underlying respiratory diseases. All trials were sponsored by the manufacturers.

Oseltamivir

Of the 23 oseltamivir trials in Stage 1, 15 were multicentre trials conducted in both the Northern and Southern Hemispheres, while eight were done in only one country (USA five, Japan two and China one). In total 9623 participants were included (6574 in treatment trials and 3049 in prophylaxis trials). The age of the participants ranged from 1 to 82 years and the duration of follow-up varied from 6 to 42 days.

Two of the trials were conducted within nursing homes; 20 were within free-living populations; one was performed in in- and out-patient departments. Three trials were conducted in children, while participants in 20 trials were adults. In some trials the eligible population included participants at increased risk of influenza complications, or with diagnoses of asthma or chronic obstructive pulmonary disease, but the majority included only otherwise healthy adults. In one trial (WV15730), participants were stratified by smoking status, while those in another trial were stratified by the presence or absence of otitis media (WV15758).

All trials compared orally administered oseltamivir (either as capsules or reconstituted powder) with placebo.

Of the 23 trials, we included 20 RCTs for the analysis examining the use of oseltamivir compared with placebo. Two were excluded from the meta-analysis because they were only synopsis reports (JV15823; JV15824) and another because it was not a full clinical study report (ML16369).

We finally included 20 oseltamivir trials into Stage 2: 11 on treatment in adults (M76001; WV15670; WV15671; WV15707, WV15730; WV15812/WV15872; WV15819/WV15876/WV15978 WV16277), four in children (NV16871; WV15758; WV15759/WV15871), and five on prophylaxis: two in adults (WV15673/WV15697), two in the elderly (WV15708; WV15825) and one in households (WV15799). Of the 15 included treatment trials of oseltamivir only three (M76001; WV15670; WV15758) were successful in recruiting the a priori planned sample size.

Zanamivir

Of the 28 included zanamivir trials, 18 were multicentre trials done in both the Northern and Southern Hemisphere and 10 were done in only one country (Japan five, USA three, Finland and Germany one each). In total 14,628 participants were included (7678 in treatment trials and 6950 in prophylaxis trials). Participants' age ranged from 5 to 12 years to over 65 and duration of follow-up varied from 5 to 35 days.  

Two of the trials were performed within nursing homes; several were within free-living populations; one was performed within a university student population. In some trials the eligible population included participants at increased risk of influenza complications, or with diagnoses of asthma or chronic obstructive pulmonary disease, but the majority included only adults who were otherwise healthy.

Zanamivir was administered as an intranasal spray, an inhalation or a combination of both and placebos were designed to match. Administration was by the participant in the majority of trials and by nursing staff in the trials within nursing homes. Twenty-two trials compared inhaled zanamivir with placebo and six trials compared inhaled zanamivir, or intranasal zanamivir, with placebo or usual care.

Of the 28 trials we included 26 RCTs for the analysis examining the use of zanamivir compared with placebo. Two were excluded from the meta-analysis because one was only a synopsis (NAI30020) and one compared zanamivir to usual care and not placebo (NAIA3003). 

We finally included 26 zanamivir trials: 14 on treatment in adults (JNAI-01; JNAI-04; JNAI-07, NAI30008; NAI30011; NAI30012; NAI30015; NAIA/B2008; NAIA2005; NAIA3002; NAIB2005; NAIB2007; NAIB3001; NAIB3002), two in children (NAI30009; NAI30028) and 10 trials in prophylaxis (167-101; NAI30034; NAIA/B2009; NAIA2006; NAIA3004; NAIA3005; NAIB2006; PE-01; NAI30010; NAI30031).

Our attempt at collecting sufficient information from regulatory files to reconstruct missing clinical study reports also failed because the information appeared insufficient for a reliable reconstruction.

Excluded studies

We excluded 123 studies from entering Stage 1 for various reasons. Some were pharmacokinetic studies, or had an active comparator, or compared higher- versus lower-dose schedules, or were ongoing trials. A further 19 trials are awaiting assessment (Characteristics of studies awaiting classification).

Risk of bias in included studies

Study level assessments are reported in the 'Risk of bias' tables. To address the problem of reporting bias, we ignored published trial reports and directed our attention to clinical study reports and regulatory information. Our problems in reviewing the copious material at our disposal were how to identify and analyse important details in the midst of thousands of pages of information and how to construct a coherent appraisal of large and complex trial programmes.

In addition, since we gained unrestricted access to the full clinical study reports (apart from personal de-identifying redactions) we took the view that all information needed to judge risk of bias should be present. Therefore when this information was not available, we judged the corresponding risk of bias element as at 'high' risk of bias. For example, when details of the random sequence generation are missing from journal publications of clinical trials, it is customary to record this as "unknown" risk of bias. This judgment usually carries the assumption that the random sequence generation details are available in more detailed reports. But when these details were still missing in even full clinical study reports, we chose to rate this risk of bias element at "high" risk of bias.

In the following paragraphs we report some of the salient findings using the current Cochrane format but applying the logic of reviewing regulatory data.

Allocation

In 10 of the 20 oseltamivir studies included in Stage 2 the description of random sequence generation is missing. The reporting of all zanamivir trials but one (NAI30028) was biased by the absence of description of random sequence generation.

Blinding

The placebo and active drug capsule cap were not identical in 11 of the 20 trials of oseltamivir. This may have compromised blinding of participants. For all but one of the zanamivir trials we did not have the certificates of analysis to enable us to reconstruct the appearance, taste and texture of the two principles.

Incomplete outcome data

In addition to the missing diary cards in three treatment trials (see Results of the search section), we were unable to identify all data for all outcomes in all oseltamivir trials and in eight of the zanamivir trials. For example, hospitalisations were not reported in zanamivir trials and inconsistently reported in oseltamivir trials. The relevant data in this review come from a table of hospitalisations sent to us by Roche in late 2013. In addition, in some trials we were unable to track individual participants through tables, narratives and individual listings. The issue of compliharms impeded the ascertainment of harms in oseltamivir treatment trials (Appendix 1). We had difficulty in following the logic of compliharms, even with access to full clinical study reports. The definition of adverse events in the RCTs of oseltamivir and zanamivir is different from the ordinary definition of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E2D guideline, which is as follows: "An adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (for example, an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product". (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2D/Step4/E2D_Guideline.pdf accessed 27 December 2013).

As an example, the definition of adverse events in the WV15671 study is as follows (PDF page 35): "following the alleviation of influenza-like symptoms, the recurrence of a single respiratory or constitutional symptom was recorded as an adverse event, however, the reappearance of more than one symptom was recorded as influenza-like syndrome (i.e. secondary illness) and therefore do not appear as adverse events" and WV15670: "any adverse change from the subject's baseline (pre-treatment) condition, which occurred during the course of the study after treatment had started, whether considered related to treatment or not". Treatment included all investigational agents (including placebo and comparative agents) administered during the course of the study)" (our emphasis). As a consequence, adverse events that are similar to the symptoms of influenza (such as headache and mild gastrointestinal adverse events) tend to be excluded from the treatment trials.

We identified a report of a site inspection for the adult prophylaxis trial WV15673/WV15697. The FDA carried out the inspection in September 2000 at various trial sites in the US including the West Virginia site (which was responsible for enrolling many hundreds of participants). An FDA official letter reported several violations including failure to report serious harms to the sponsor (Roche) as the protocol required and in addition stated: "... we view the statement in the payment section of the consent form used in the study that subjects '...will receive $300.00 for participating in and completing the study. No payment will be made to you if you withdraw from the study for personal reasons...' to be an improper procedure. When subjects are to be paid for participating in a study, the payment should be prorated for the subject's actual participation in the study in order to avoid the possibility of coercion" (FDA 2000e, PDF page 177). However, the FDA allowed the data (which had been published a year earlier in a prime journal) to stand in support of Roche's application for the prophylaxis indication. We do not know whether the participant contract was standard (i.e. whether the observation of possible improper procedures could be generalised to other sites and other trials), but the document cited by the FDA inspector is the subject of one of our (as yet unfulfilled) Freedom of Information (FOI) requests. The possibility of financial pressure, if confirmed, could seriously confound drop-out rates because of harms or any other causes in prophylaxis trials.

The significantly higher incidence of diarrhoea in placebo recipients of treatment trial WV15671 was identified by the FDA reviewers who remarked "Diarrhea was reported more frequently among subjects receiving placebo than among subjects receiving Ro 64-0796 [oseltamivir]. Diarrhoea, although not specified as an inclusion criterion, has been documented to be a clinical manifestation of influenza infection. The reduction in the incidence of diarrhoea for the treatment groups compared with the placebo group could be considered as a possible treatment effect of Ro 64-0796" (FDA 1999c). However, according to the Japanese Summary Basis for Approval (JSBA) of oseltamivir capsules for prophylaxis, diarrhoea was reported more frequently in the oseltamivir arm (49/986) than in the placebo group (38/973) in the summarised table of adverse events from three trials (WV15673/WV15697; WV15708; WV15825). Our findings are inconsistent with the explanation by the FDA.

Selective reporting

All oseltamivir trials and almost half of the zanamivir trials had selected reporting. The oseltamivir trials showed a consistent trend of missing original protocols (except for M76001), changing outcome definitions while the trial was running, protocol amendments even after the trial had been completed, inconsistent approaches to outcome data collection, missing statistical analysis plans, missing date of unblinding and the use of self reported outcomes such as pneumonia (M76001; WV15670; WV15671; WV15707; WV15730; WV16277). This represent 55% of pneumonia event data. As an example, in trial WV15670, secondary illnesses were patient reported. The body of the clinical study report states that complications requiring antibiotic treatment were specified a priori but even in the final version of the protocol, for which we have the full text, there is no predefined list of secondary illnesses (i.e. no mention of pneumonia, bronchitis, sinusitis or otitis in the protocol), nor did complications have anything to do with antibiotic treatment according to the protocol, nor does the Case Report Form mention specific secondary illnesses by name. Zanamivir trials reported outcomes not specified in the protocol provided.

We found evidence of possible selective reporting bias when we analysed the JSBA data on prophylaxis. The regulatory data reports tables for individual trials as well as 10 pages of summarised tables for three trials of prophylaxis (WV15673/WV15697; WV15708; WV15825). Tables for individual trials include data for high-dose arms but report few psychiatric adverse events overall. However, the summarised tables list a variety of psychiatric adverse events including psychotic and suicidal adverse events, but not adverse events from the high-dose group. As a preliminary exploratory analysis, we combined the following suspected serious adverse events collectively: hallucination and delusion that are classified grade 3 (serious) by the National Cancer Institute-Common Toxicity Criteria Version 2.0 (NCI-CTC V2.0), psychosis (hallucination and delusion are the two major symptoms of this disease), suicidal attempt that is classified grade 3 (serious) by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (CTCAE V4.0) and hostility that includes aggression, hostility, violence, murder and commonly considered as serious events though not listed in the NCI-CTC V2.0 or CTCAE V4.0. Numbers of suspected serious psychotic/suicidal adverse events (including hallucination, psychosis, schizophrenia, paranoia, aggression/hostility and attempted suicide) were five in the oseltamivir group and zero in the placebo group during the on-treatment period. When the off-treatment period data are added the total was eight versus one. The prophylaxis programme is crucial in understanding the harms profile of the drug as the potential for harms witnessed to be confounded by the apparently numerous symptoms and signs of influenza infection is far less, as many participants do not become infected with influenza. This makes a causality assessment more straightforward.

Other potential sources of bias

All but three of the oseltamivir treatment trials were under-recruited. Several of the zanamivir trials were also under-recruited. We noted the use of different relief medication across different centres within the same trial and in one zanamivir trial (NAI30031), according to the protocol participants receiving antibiotics for bacterial respiratory tract infection should have been excluded but in the trial this did not happen. In the zanamivir trial NAI30034, the definition of "confirmed influenza" was amended after protocol closure.

We also noted several other items that were not included in all full clinical study reports:

  • Study protocols dated prior to participant enrolment (missing for many oseltamivir trials).

  • Certificates of analysis for the intervention/placebo preparations.

  • Patient enrolment dates explicitly reported (only trial inception and cessation dates are given; in zanamivir trials these are partially redacted).

  • Explicitly reported date of trial unblinding. We frequently noted the statement "the database was authorized on xxxx" to identify the unblinding date but an explicit date is important to report. In some cases, the date of unblinding was reported but the actual date within the month was redacted. This practice also applied to zanamivir protocol amendments.

  • Authorship and accountability for the writing of the clinical study reports.

  • Statistical analysis plans in some cases.

  • Patient consent forms (missing from most zanamivir trials).

  • Patient information form (missing from most zanamivir trials).

  • List of randomisation codes (variably included).

  • Case report form templates in zanamivir trials do not allow for determining who completes the form (patient or clinician).

  • Core data sheet.

Other important documents that we did not have included:

  • Study manual of procedures.

  • Minutes of safety data monitoring committee meetings.

The placebo interventions in both sets of trials may have contained active substances. The placebo for zanamivir trials contained lactose powder, which can potentially cause bronchospasm, while the placebo for oseltamivir trials contained dehydrocholic acid and dibasic calcium phosphate dehydrate, which can cause gastrointestinal symptoms.

Data on participants by influenza-infected status (in treatment trials) and for participants with influenza-like illness (in prophylaxis trials) were not reported in the oseltamivir clinical study reports.

Finally, data on the effects of rescue or relief medication (mainly paracetamol/acetaminophen) were incomplete in clinical study reports of oseltamivir trials and not reported separately in all zanamivir trials.

Effects of interventions

Analysis of time to first symptom alleviation

In adult treatment, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, I2 statistic = 0%), representing a 10% reduction from 7 days to 6.3 days (Analysis 1.1; Figure 4). There was no significant effect in asthmatic children: increased by 5.2 hours (95% CI 11.1 hours lower to 21.4 hours higher, I2 statistic = 0%). But there was an effect in otherwise healthy children, based on one trial: 29 hours, 95% CI: 12 to 47 hours, P = 0.001). (Analysis 1.46). Zanamivir reduced time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days, I2 statistic = 9%), which equates to a 14.4 hours (10%) reduction in symptoms from 6.6 days to 6.0 days (Analysis 3.1; Figure 5). There was no significant effect in children: time to first alleviation of symptoms was 1.08 days lower in the zanamivir group (95% CI 2.32 lower to 0.15 days higher, I2 statistic = 72%) (Analysis 3.14).

Figure 4.

Forest plot of comparison: 1 Oseltamivir versus placebo for treatment, outcome: 1.1 Time to first alleviation of symptoms in adult treatment (ITT population) [hours].

Figure 5.

Forest plot of comparison: 3 Zanamivir versus placebo for treatment, outcome: 3.1 Time to first alleviation of symptoms in adult treatment (days).

In eight zanamivir trials that reported on use of relief medication, in all participants the median days to alleviation in both the placebo and the treatment arms was less when compared to those who did not use relief medications (Table 6). In seven zanamivir trials, time to first alleviation of symptoms was also reported with and without rescue medication. Using these data we were able to compare zanamivir without rescue medication with placebo with rescue medication. Overall there was a non-significant 0.41 day decrease (95% CI 0.47 days lower to 1.29 days higher, I2 statistic = 67%) in time to first alleviation of symptoms in the placebo with rescue medication group, suggesting that zanamivir itself is no better than rescue medication and possibly even less effective, although the varying levels of use of rescue medication in the seven trials did give rise to large heterogeneity (Analysis 3.68; Figure 6).

Figure 6.

Forest plot of comparison: 3 Zanamivir versus placebo for treatment, outcome: 3.68 Time to first alleviation of symptoms in adults with/without relief medication [days].

Table 6. Time to alleviation* of clinically significant symptoms of influenza-like illness (in all participants and participants with no use of relief medication)
  1. *Alleviation defined as no fever (temperature < 37.8 °C), cough recorded as none or mild and muscle/joint aches and pains, sore throat, feverishness/chills and headache recorded as absent/minimal

Study Sample size Median days to alleviation for all participants

Difference in days

(P value)

Median days to alleviation and no use of relief medication Difference in days (P value)
  Zanamivir (n) Placebo (n) Zanamivir Placebo  Zanamivir Placebo 
NAI300082622636.07.0

1.0

(0.123)

8.010.0

2.0

(0.037)

NAI300092242474.55.0

0.5

(0.011)

5.06.0

1.0

(0.002)

NAI3001076814.55.5

1.0

(0.033)

5.56.75

1.25

(0.150)

NAI300112372294.505.00

0.50

(0.495)

7.07.0

0.0

(0.623)

NAI300121911676.57.5

1.0

(0.159)

9.010.0

1.0

(0.131)

NAI300152932952.172.67

0.5

(0.166)

3.173.83

0.66

(0.058)

NAIA30024123655.56.0

0.5

(0.228)

7.08.0

1.0

(0.054)

NAIB30021741825.07.5

2.5

(< 0.001)

5.58.252.75 (< 0.001)

In subgroup analysis of time to first alleviation of symptoms in adults by infection status, we found no evidence of a difference in treatment effect for zanamivir on the influenza-infected subgroup compared to the non-influenza-infected subgroup (P = 0.53). The treatment effect was 0.67 days (95% CI 0.35 to 0.99 days, I2 statistic = 17%) for influenza-infected patients and 0.52 days (95% CI 0.18 to 0.86 days, I2 statistic = 0%) for non-influenza-infected patients (Analysis 3.69).

Analysis of hospitalisations

In oseltamivir treatment of adults, there was no significant difference in hospitalisation rate between treatment groups (risk ratio (RR) 0.92, 95% CI 0.57 to 1.50, I2 statistic = 0%) (Analysis 1.2), or in treatment of children (RR 1.92, 95% CI 0.70 to 5.23, I2 statistic = 0%) (Analysis 1.47 ), with wide CIs; or in prophylaxis (RR 1.14, 95% CI 0.66 to 1.94, I2 statistic = 0%) (Analysis 2.7). Data on hospitalisations for the zanamivir studies were not reported.

Analysis of influenza complications

Pneumonia

In adult treatment trials, oseltamivir significantly reduced self reported, investigator-mediated, unverified pneumonia (RR 0.55, 95% CI 0.33 to 0.90, I2 statistic = 0%; risk difference (RD) 1.00%, 95% CI 0.22 to 1.49; number needed to treat to benefit (NNTB) = 100, 95% CI 67 to 451) in the treated population. The effect was significant in the six trials that collected data on non-specific adverse events or secondary/intercurrent illness forms (RR 0.44, 95% CI 0.22 to 0.88, I2 statistic = 0%; RD 0.99%, 95% CI 0.21 to 1.38; NNTB = 101, 95% CI 73 to 470). However, it was not significant in the five trials (two clinical study reports) that used more detailed diagnostic data collection forms, and in no studies that reported on radiological confirmation of pneumonia (Figure 7; Analysis 1.17). There was no significant effect on pneumonia in children (RR 1.06, 95% CI 0.62 to 1.83, I2 statistic = 0%) (Analysis 1.52). In two zanamivir adult trials (NAI30012; NAI30015), pneumonia reporting was based on a stricter definition of X-ray confirmation and there was also no significant treatment effect (RR 1.02, 95% CI 0.35 to 3.02, I2 = 39%) (Analysis 3.3). In nine zanamivir trials (NAI30008; NAI30010; NAI30011; NAIA/B2008; NAIA2005; NAIA3002; NAIB2007; NAIB3001; NAIB3002), pneumonia was a self reported, investigator-mediated, unverified outcome (Figure 8; Figure 9). Overall, there was no significant effect of zanamivir on mixed verified and unverified pneumonia in adult treatment (RR 0.90, 95% CI 0.58 to 1.40, I2 statistic = 0%) (Analysis 3.2). Analysis 4.5 shows that in prophylaxis trials, zanamivir reduced the risk of self reported, investigator-mediated, unverified pneumonia in adults (RR 0.30, 95% CI 0.11 to 0.80, I2 statistic = 0%; RD 0.32%, 95% CI 0.09 to 0.41; NNTB = 311, 95% CI 244 to 1086).

Figure 7.

Forest plot of comparison: 1 Oseltamivir versus placebo for treatment, outcome: 1.17 Complications: pneumonia in adult treatment.

Figure 8.

Example Diary card from case-report form for Zanamivir trial

Figure 9.

Example Diary card from case-report form for Zanamivir trial (cont)

In meta-regression of 'pneumonia' based on 32 studies, treatment effects were not statistically different by age group (P = 0.22), drug (P = 0.89) or indication (P = 0.14). However, treatment effects were statistically different by method of diagnosis (P = 0.025). For unclear objective diagnosis of pneumonia, the treatment effect was RR 0.51 (95% CI 0.35 to 0.75, I2 statistic = 0%), whereas for objective diagnosis data collection of pneumonia, the treatment effect was 1.01 (95% CI 0.69 to 1.47, I2 statistic = 0%). A subgroup analysis of pneumonia for all 32 studies by method of diagnosis is shown in Analysis 5.1. Please note that estimates in the subgroup analysis are slightly different to those obtained in meta-regression due to the different methodologies.

Serious complications and study withdrawals

In oseltamivir trials, treatment did not significantly affect complications classified as serious or those that led to withdrawal from the trial in adults (RR 0.91, 95% CI 0.40 to 2.06, I2 statistic = 0%) (Analysis 1.20) or in children (RR 1.98, 95% CI 0.58 to 6.72, I2 statistic = 0%) (Analysis 1.55). This outcome could not be assessed in oseltamivir prophylaxis due to an insufficient number of events. There was no significant effect of zanamivir, in adult treatment, in reducing the risk of any complication classified as serious or which led to study withdrawal (RR 1.10, 95% CI 0.46 to 2.63, I2 statistic = 0%) (Analysis 3.7) or in prophylaxis (RR 1.09, 95% CI 0.36 to 3.26, I2 statistic = 0%) (Analysis 4.8). This outcome could not be assessed in children due to an insufficient number of events.

Bronchitis, sinusitis and otitis media

Neither zanamivir (Analysis 4.6; Analysis 4.7) nor oseltamivir (Analysis 2.8; Analysis 2.9) significantly reduced the risk of bronchitis or sinusitis in prophylaxis trials. In adults, treatment with oseltamivir did not significantly reduce the risk of bronchitis (RR 0.75, 95% CI 0.56 to 1.01, I2 statistic = 36%) (Analysis 1.16), sinusitis (RR 1.03, 95% CI 0.76 to 1.40, I2 statistic = 0%) (Analysis 1.18) or otitis media (RR 1.11, 95% CI 0.57 to 2.15, I2 statistic = 0%) (Analysis 1.19). The result for bronchitis was sensitive to the methods used, as a fixed-effect analysis showed a significant effect (P = 0.02). Oseltamivir did not significantly affect complications in treatment of children (Analysis 1.52 ; Analysis 1.50; Analysis 1.53), including otitis media (RR 0.80, 95% CI 0.62 to 1.02, I2 statistic = 0%) (Analysis 1.51).

Treatment with zanamivir significantly reduced the risk of bronchitis in adults (RR 0.75, 95% CI 0.61 to 0.91, I2 statistic = 0%; RD 1.80%, 95% CI 0.65 to 2.80; NNTB = 56, 95% CI 36 to 155) (Analysis 3.4), but did not reduce the risk of sinusitis (Analysis 3.5) or otitis media (Analysis 3.6). In children, zanamivir treatment did not significantly reduce the risk of sinusitis (RR 0.87, 95% CI 0.12 to 6.45, I2 statistic = 40%) (Analysis 3.17) or otitis media (RR 1.00, 95% CI 0.59 to 1.72, I2 statistic = 0%) (Analysis 3.18).

See Table 1 for a summary of the methodology used for collecting and assessing complications in oseltamivir treatment trials. See Table 7 for the overall results for oseltamivir in adults and Table 8 for children. See Table 9 for the overall results for zanamivir in adults and Table 10 for children.

Table 7. Oseltamivir versus placebo for treating influenza in healthy adults
Oseltamivir versus placebo for treating influenza in healthy adults
Patient or population: healthy adults with influenza
Settings: community, nursing homes
Intervention: oseltamivir versus placebo for treatment
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Risk difference (95% CI)NNTB or NNTH (95% CI)
Assumed riskCorresponding risk
Placebo Oseltamivir versus placebo for treatment
Time to first alleviation of symptoms in adult treatment (ITT population) (hours) The mean time (hours) to first alleviation of symptoms adults in the intervention groups was
16.76 lower
(25.1 to 8.42 lower)
16.8 hours (8.4 to 25.1)3954
(8)
N/AN/A
Adverse events: nausea in adult treatment (on-treatment) Study population RR 1.57
(1.14 to 2.15)
4452
(8)
-3.66% (-7.39 to -0.9)NNTH = 28 (14 to 112)
64 per 1000 101 per 1000
(73 to 138)
Adverse events: vomiting in adult treatment (on-treatment) Study population RR 2.43
(1.75 to 3.38)
4452
(8)
-4.56% (-7.58 to -2.39)NNTH = 22 (14 to 42)
32 per 1000 77 per 1000
(56 to 108)
Adverse events: diarrhoea in adult treatment (on-treatment) Study population RR 0.67
(0.46 to 0.98)
4452
(8)
2.33% (0.14 to 3.81)NNTB = 43 (27 to 709)
71 per 1000 47 per 1000
(32 to 69)
Complications: self reported, investigator-mediated, unverified pneumonia in adult treatment Study population RR 0.55
(0.33 to 0.90)
4452
(8)
1.00% (0.22 to 1.49)NNTB = 100 (67 to 451)
22 per 1000

12 per 1000

(7 to 20)

Adverse events: cardiac body system in adult treatment (on-treatment) Study population RR 0.49
(0.25 to 0.97)
3943
(6)
0.68% (0.04 to 1.00)NNTB = 148 (101 to 2509)
13 per 1000 7 per 1000
(3 to 13)
Adverse events: hospital admission in adult treatment Study population

RR 0.92

(0.57 to 1.50)

4394

(7)

0.15% (-0.78 to 0.91)NNTB = 687 (NNTB 110 to ∞ to NNTH 128)
18 per 1000

17 per 1000

(11 to 28)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Negative risk differences indicate harms; positive risk differences indicate benefits.
CI: confidence interval; RR: risk ratio; NNTB: number needed to treat to benefit; NNTH: number needed to treat to harm
 
Table 8. Oseltamivir versus placebo for treating influenza in healthy children
Oseltamivir versus placebo for treating influenza in healthy children
Patient or population: healthy children with influenza
Settings: community
Intervention: oseltamivir versus placebo for treatment
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Risk difference (95% CI)Comments
Assumed riskCorresponding risk
Placebo Oseltamivir versus placebo for treatment
Time to first alleviation of symptoms in child treatment (hours) The mean time (hours) to first alleviation of symptoms in children in the intervention groups was
8.04 lower
(33.34 lower to 17.26 higher)
 1329
(3)
 Not significant
Hospital admission in child treatment (safety population) Study population RR 1.92
(0.7 to 5.23)
1359
(3)
-0.81% (-3.72 to 0.26)NNTH = 124 (NNTB 379 to ∞ to NNTH 27)
9 per 1000 17 per 1000
(6 to 46)
Complications: bronchitis in child treatment Study population RR 0.65
(0.27 to 1.55)
1359
(3)
1.08% (-1.69 to 2.25)NNTB = 93 (NNTB 45 to ∞ to NNTH 59)
31 per 1000 20 per 1000
(8 to 48)
Complications: otitis media in child treatment Study population RR 0.8
(0.62 to 1.02)
1359
(3)
3.26% (-0.33 to 6.18)NNTB = 31 (NNTB 17 to ∞ to NNTH 308)
163 per 1000 130 per 1000
(101 to 166)
Complications: pneumonia in child treatment Study population RR 1.06
(0.62 to 1.83)
1359
(3)
-0.22% (-3.07 to 1.41)NNTH = 450 (NNTB 71 to ∞ to NNTH 33)
37 per 1000 39 per 1000
(23 to 68)
Adverse events: diarrhoea in child treatment (on-treatment) Study population RR 0.87
(0.58 to 1.28)
1358
(3)
0.93% (-2.01 to 3.02)NNTB 108 (NNTB 34 to ∞ to NNTH 50)
72 per 1000 63 per 1000
(42 to 92)
Adverse events: vomiting in child treatment (on-treatment) Study population RR 1.7
(1.23 to 2.35)
1358
(3)
5.34% (1.75 to 10.29)NNTH = 19 (10 to 57)
76 per 1000 130 per 1000
(94 to 179)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Negative risk differences indicate harm; positive risk differences indicate benefits.
CI: confidence interval; RR: risk ratio; NNTB: number needed to treat to benefit; NNTH: number needed to treat to harm
Table 9. Zanamivir versus placebo for treating influenza in healthy adults
Zanamivir versus placebo for treating influenza in healthy adults
Patient or population: healthy adults with influenza
Settings: community, nursing homes
Intervention: zanamivir versus placebo for treatment
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Risk difference (95% CI)NNTB or NNTH (95% CI)
Assumed riskCorresponding risk
Placebo Zanamivir versus placebo for treatment
Time to first alleviation of symptoms in adult treatment (days) The mean time (days) to first alleviation of symptoms in adults in the intervention groups was
0.60 lower
(0.81 to 0.39 lower)
0.60 days (0.39 to 0.81)5411
(13)
N/AN/A
Complications: pneumonia confirmed with X-ray in adult treatment Study population RR 1.02
(0.35 to 3.02)
946
(2)
-0.06% (-6.56 to 2.11)NNTH = 1540 (NNTB 48 to ∞ to NNTH 16)
32 per 1000 33 per 1000
(11 to 98)
Adverse events: nausea/vomiting in adult treatment (on-treatment) Study population RR 0.6
(0.39 to 0.94)
6553
(15)
1.63% (0.24 to 2.48)NNTB = 62 (41 to 411)
41 per 1000 24 per 1000
(16 to 38)
Adverse events: psychiatric body system in adult treatment (on-treatment) Study population RR 1.16
(0.57 to 2.38)
4732
(10)
-0.09% (-0.76 to 0.24)NNTH 1132 (NNTB 421 to ∞ to NNTH 132)
6 per 1000 6 per 1000
(3 to 13)
Complications: bronchitis in adult treatment Study population

RR 0.75

(0.61 to 0.91)

6072

(12)

1.80% (0.65 to 2.80)NNTB 56 (36 to 155)
72 per 1000

54 per 1000

(44 to 65)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Negative risk differences indicate harms; positive risk differences indicate benefits.
CI: confidence interval; RR: risk ratio; NNTB: number needed to treat to benefit; NNTH: number needed to treat to harm
 
Table 10. Zanamivir versus placebo for treating influenza in healthy children
Zanamivir versus placebo for treating influenza in healthy children
Patient or population: healthy children with influenza
Settings: community
Intervention: zanamivir versus placebo for treatment
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Risk difference (95% CI)NNTB or NNTH (95% CI)
Assumed riskCorresponding risk
Placebo Zanamivir versus placebo for treatment
Time to first alleviation of symptoms in children (days) The mean time (days) to first alleviation of symptoms in children in the intervention groups was
1.08 lower
(2.32 lower to 0.15 higher)
 723
(2)
NANA
Complications: sinusitis in child treatment Study population RR 0.87
(0.12 to 6.45)
737
(2)
0.19% (-8.09 to 1.31)NNTB = 519 (NNTB 13 to ∞ to NNTH 77)
15 per 1000 13 per 1000
(2 to 96)
Complications: otitis media in child treatment Study population RR 1.0
(0.59 to 1.72)
737
(2)
0.00% (-5.13 to 2.92)NNTB = > 1000 (NNTB 35 to ∞ to NNTH 20)
71 per 1000 71 per 1000
(42 to 122)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Negative risk differences indicate harms; positive risk differences indicate benefits.
CI: confidence interval; RR: risk ratio; NNTB: number needed to treat to benefit; NNTH: number needed to treat to harm

Analysis of influenza outcomes in prophylaxis studies

Symptomatic influenza was lower in the oseltamivir arms compared to placebo in studies of prophylaxis (RR 0.45, 95% CI 0.30 to 0.67, I2 statistic = 0%; RD 3.05%, 95% CI 1.83 to 3.88; NNTB = 33, 95% CI 26 to 55) (Analysis 2.1); but there were no differences for all other influenza outcomes including overall influenza-like-illness reported as an adverse event on-treatment. In household prophylaxis, one small study with missing outcome data and selective reporting, including 405 participants, showed a significant reduction of symptomatic influenza in the oseltamivir arm compared to placebo (RR 0.20, 95% CI 0.09 to 0.44; RD 13.6%, 95% CI 9.52 to 15.47) (Analysis 2.3), but in the same study there was no significant reduction in asymptomatic influenza (RR 1.14, 95% CI 0.39 to 3.33) (Analysis 2.4). Asymptomatic influenza was not significantly reduced and there was no non-influenza, influenza-like illness reported throughout the study period.

In prophylaxis trials we could not analyse effects on influenza-like illness because of a lack of definition in the clinical study reports. However, using our definition (see methods), oseltamivir did not reduce influenza-like illness in participants (RR 0.95, 95% CI 0.86 to 1.06).

The Roche trial programme assessing the effects of oseltamivir in post-exposure prophylaxis (PEP) submitted to the FDA on 22 May 2000 consisted of two trials: WV15799 and WV16139. We included only trial WV15799 because WV16139 was not placebo-controlled. WV15799 was a double-blind, cluster-randomised trial in which contact clusters of index cases were randomised to oseltamivir 75 mg a day or placebo for seven days. The manufacturer concluded that the trial proved that oseltamivir could prevent influenza in contacts by interrupting transmission from index cases. Interruption of transmission has two components: reduction of viral spread from index cases (measured by nasal shedding of influenza viruses) and prevention of onset of influenza in contacts measured with a mixture of symptoms and signs and 'laboratory confirmation' (i.e. viral culture from the upper airways and/or at least a four-fold rise in antibody titres measured between baseline and two to three weeks later). The design of the WV15799 is weak. All index cases were left untreated except for a paracetamol rescue pack, making it impossible to assess the effect of oseltamivir on nasal voidance of index cases. Nasal viral voidance was measured only in symptomatic participants thereby missing out on potential asymptomatic infected people.

Zanamivir similarly significantly reduced the risk of symptomatic influenza for individuals (RR 0.39, 95% CI 0.22 to 0.70, I2 statistic = 45%; RD = 1.98%, 95% CI: 0.98 to 2.54; NNTB = 51, 95% CI 40 to 103) (Analysis 4.1), as well as households (RR 0.33, 95% CI 0.18 to 0.58, I2 statistic = 40%; RD = 14.84%, 95% CI 12.18 to 16.55, NNTB = 7, 95% CI 6 to 9) (Analysis 4.3). However, it did not reduce the risk of asymptomatic influenza in the prophylaxis of individuals (RR 0.97, 0.76 to 1.24, I2 statistic = 0%) (Analysis 4.2) or asymptomatic individuals in post-exposure prophylaxis of households (RR 0.88, 95% CI 0.65 to 1.20, I2 statistic = 0%) (Analysis 4.4). See Table 11 for the overall results for oseltamivir in adults and Table 9 for children. See Table 12 and Table 13 for the overall results for zanamivir in adults and Table 14 for children.

Table 11. Oseltamivir versus placebo for preventing influenza in healthy children
Oseltamivir versus placebo for preventing influenza in healthy children
Patient or population: healthy children without influenza
Settings: community
Intervention: oseltamivir versus placebo for prophylaxis
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Comments
Assumed riskCorresponding risk
Placebo Oseltamivir versus placebo for treatment
No data
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
Table 12. Zanamivir versus placebo for preventing influenza in healthy adults
Zanamivir versus placebo for preventing influenza in healthy adults
Patient or population: healthy adults without influenza
Settings: community, nursing homes
Intervention: zanamivir versus placebo for prophylaxis
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Risk difference (95% CI)NNTB or NNTH (95% CI)
Assumed riskCorresponding risk
Placebo Zanamivir versus placebo for prophylaxis
Symptomatic influenza in prophylaxis of individuals Study population

RR 0.39

(0.22 to 0.70)

5275

(4)

1.98% (0.98 to 2.54)NNTB = 51 (40 to 103)
33 per 1000 13 per 1000
(7 to 23)
Asymptomatic influenza in prophylaxis of individuals Study population RR 0.97
(0.76 to 1.24)
5275
(4)
0.14% (-1.1 to 1.1)NNTB = 729 (NNTB 91 to ∞ to NNTH 91)
50 per 1000 48 per 1000
(38 to 60)
Symptomatic influenza in household prophylaxis Study population RR 0.22
(0.13 to 0.36)
824
(2)
14.84% (12.18 to 16.55)NNTB = 7 (6 to 9)
190 per 1000 42 per 1000
(25 to 68)
Asymptomatic influenza in household prophylaxis Study population RR 0.90
(0.6 to 1.35)
824
(2)
1.32% (-2.2 to 3.84)NNTB = 76 (NNTB 26 to ∞ to NNTH 46)
107 per 1000 97 per 1000
(64 to 145)
Complications: pneumonia in adult prophylaxis Study population RR 0.30
(0.11 to 0.8)
7662
(6)
0.32% (0.09 to 0.41)NNTB = 311 (244 to 1086)
5 per 1000 1.5 per 1000
(1 to 4)
Complications: bronchitis in adult prophylaxis Study population

RR 0.49

(0.02 to 1.19)

7662

(6)

0.79% (-0.29 to 1.24)NNTB = 127 (to NNTB 81 to ∞ to NNTH 341)
15 per 1000

8 per 1000

(3 to 18)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Negative risk differences indicate harms; positive risk differences indicate benefits.
CI: confidence interval; RR: risk ratio; NNTB: number needed to treat to benefit; NNTH: number needed to treat to harm
 
Table 13. Oseltamivir versus placebo for preventing influenza in healthy adults
Oseltamivir versus placebo for preventing influenza in healthy adults
Patient or population: healthy adults without influenza
Settings: community, nursing homes
Intervention: oseltamivir for prophylaxis
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Risk difference (95% CI)NNTB or NNTH (95% CI)
Assumed riskCorresponding risk
Placebo Oseltamivir versus placebo for prophylaxis
Symptomatic influenza in adult prophylaxis of individuals Study population RR 0.45
(0.30 to 0.67)
2479
(3)
3.05% (1.83 to 3.88)NNTB = 33 (26 to 55)
55 per 1000 25 per 1000
(17 to 37)
Symptomatic influenza in household prophylaxis Study population RR 0.2
(0.09 to 0.44)
405
(1)
13.6% (9.52 to 15.47)NNTB = 7 (6 to 11)
170 per 1000 34 per 1000
(15 to 75)
Adverse events: psychiatric body systems in adult prophylaxis (all events on- and off-treatment) Study population RR 1.80
(1.05 to 3.08)
3434
(4 studies)
-1.06% (-2.76 to -0.07)NNTH = 94 (36 to 1538)
13 per 1000 23 per 1000
(14 to 40)
Adverse events: headache in adult prophylaxis (on-treatment) Study population RR 1.18
(1.05 to 1.33)
3434
(4)
-3.15% (-5.78 to -0.88)NNTH = 32 (18 to 115)
175 per 1000 207 per 1000
(184 to 233)
Adverse events: nausea in adult prophylaxis (on-treatment) Study population RR 1.96
(1.2 to 3.2)
3434
(4)
-4.15% (-9.51 to -0.86)NNTH = 25 (11 to 116)
43 per 1000 85 per 1000
(52 to 138)
Adverse events: vomiting in adult prophylaxis (on-treatment) Study population RR 1.91
(0.7 to 5.22)
3434
(4)
-0.95% (-4.41 to 0.31)NNTH = 106 (NNTB 319 to ∞ to NNTH 23)
10 per 1000 20 per 1000
(7 to 55)
Adverse events: headache in adult prophylaxis (off-treatment) Study population RR 0.88
(0.63 to 1.24)
3434
(4)
0.44% (-0.89 to 1.37)NNTB = 226 (NNTB 74 to ∞ to NNTH 113)
37 per 1000 33 per 1000
(23 to 46)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Negative risk differences indicate harms; positive risk differences indicate benefits.
CI: confidence interval; RR: risk ratio; NNTB: number needed to treat to benefit; NNTH: number needed to treat to harm
 
Table 14. Zanamivir versus placebo for preventing influenza in healthy children
Zanamivir versus placebo for preventing influenza in healthy children
Patient or population: healthy children without influenza
Settings: community
Intervention: zanamivir versus placebo for prophylaxis
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Comments
Assumed riskCorresponding risk
Placebo Zanamivir versus placebo for treatment
No data
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio

Analysis of harms

Oseltamivir treatment
Nausea, vomiting and diarrhoea

Oseltamivir in the treatment of adults is associated with increased risk of nausea (RR 1.57, 95% CI 1.14 to 2.15, I2 statistic = 43%; RD 3.66%, 95% CI 0.90 to 7.39; number needed to treat to harm (NNTH) = 28, 95% CI 14 to 112) (Analysis 1.5) and vomiting (RR 2.43, 95% CI 1.75 to 3.38, I2 statistic = 12%; RD 4.56%, 95% CI 2.39 to 7.58; NNTH = 22, 95% CI 14 to 42) (Analysis 1.6). It is associated with a decreased risk of diarrhoea (RR 0.67, 95% CI 0.46 to 0.98, I2 statistic = 44%; RD 2.33%, 95% CI 0.14 to 3.81; NNTB = 43, 95% CI 27 to 709) (Analysis 1.7) when compared to placebo during on-treatment periods. Both nausea and vomiting were associated with significant heterogeneity where treatment effects appeared larger in otherwise healthy adults compared to the elderly and the chronically ill. However, one trial of otherwise healthy adults also showed smaller effects (WV16277). Vomiting was more common in those children on oseltamivir treatment compared to those on placebo (RR 1.70, 95% CI 1.23 to 2.35, I2 statistic = 0%; RD 5.34%, 95% CI 1.75 to 10.29; NNTH = 19, 95% CI 10 to 57) (Analysis 1.63).

Cardiac effects

The cardiac effects of oseltamivir are unclear. Exposure to oseltamivir may reduce cardiac general events compared to placebo (RR 0.49, 95% CI 0.25 to 0.97, I2 statistic = 0%; RD 0.68%, 95% CI 0.04 to 1.00; NNTB = 148, 95% CI 101 to 2509), excluding WV16277 in which ECG was included in the safety parameters (Analysis 1.27). However, exposure to oseltamivir may increase QTc prolongation (including borderline) as reported in trial WV16277 (RD 4.0%, 95% CI 0.71 to 7.30; NNTH = 25, 95% CI 14 to 140) compared to placebo during on-treatment periods.

Psychiatric effects

In treatment trials, there was no significant increase in risk between oseltamivir and on-treatment psychiatric adverse events overall (Analysis 1.32). However, there was a dose-response effect in the two "pivotal" treatment trials. In the identically designed trials WV15670 and WV15671 there were two active treatment groups: 150 mg (standard dose) and 300 mg (high dose) oseltamivir per day. In the dose-response analysis there was an increased risk of psychiatric body system adverse events over the entire follow-up period (P = 0.038 based on likelihood ratio test). In trial WV15670, the event rates were: 1/204, 1/206 and 4/205 in the placebo, 75 mg and 150 mg arms respectively, whereas trial WV15671 had rates of 2/235, 0/242 and 5/242, respectively.

Effect on antibodies (post-protocol hypotheses)

The proportion of patients being diagnosed as influenza-infected in oseltamivir treatment of adults was significantly lower in the treated compared to the control group (RR 0.95, 95% CI 0.91 to 0.99, I2 statistic = 0%) (Analysis 1.3). The proportion of patients with four-fold increases in antibody titre was significantly lower in the treated group compared to the control group (RR 0.92, 95% CI 0.86 to 0.97, I2 statistic = 0%) (Analysis 1.4). This represents an absolute difference of 5% between treatment groups. There was a lower proportion of children on oseltamivir with a four-fold increase in antibodies (RR 0.90, 95% CI 0.80 to 1.00, I2 statistic = 0%) (Analysis 1.49).

Oseltamivir prophylaxis
Headaches and nausea

In oseltamivir prophylaxis, there was an increased risk of headaches on-treatment (RR 1.18, 95% CI 1.05 to 1.33, I2 statistic = 0%; RD 3.15%, 95% CI 0.88 to 5.78; NNTH = 32, (95% CI 18 to 115) (Analysis 2.19; Figure 10) and nausea on-treatment (RR 1.96, 95% CI 1.20 to 3.20, I2 statistic = 49%; RD 4.15%, 95% CI 0.86 to 9.51; NNTH = 25, 95% CI 11 to 116) (Analysis 2.20). There was also a dose-response effect for headaches in study WV15673/WV15697 (P = 0.013 based on likelihood ratio test), where on-treatment rates were: 202/519, 225/520 and 242/520 in the placebo, standard-dose and high-dose arms, respectively.

Figure 10.

Forest plot of comparison: 2 Oseltamivir versus placebo for prophylaxis, outcome: 2.19 Adverse events: headache in adult prophylaxis (on-treatment).

Psychiatric effects

Figure 11 (Analysis 2.54) shows that in prophylaxis trials of oseltamivir there was a significant increase in patients with psychiatric adverse events over the on- and off-treatment periods (RR 1.80, 95% CI 1.05 to 3.08, I2 statistic = 0%; RD 1.06%, 95% CI 0.07 to 2.76; NNTH = 94, 95% CI 36 to 1538). Initial analysis of patients with psychiatric adverse events in the on-treatment period showed a borderline statistically significant result (P = 0.06), hence we conducted sensitivity analysis using Peto's method (P = 0.05) as well as the analysis reported in Figure 11.

Figure 11.

Forest plot of comparison: 2 Oseltamivir versus placebo for prophylaxis, outcome: 2.54 Adverse events: psychiatric body system in adult prophylaxis (on- and off-treatment).

Table 15 shows a summary of all psychiatric adverse events in oseltamivir prophylaxis trials. Of particular note was an oseltamivir patient in study WV15825 who had severe confusion on day 27 and was hospitalised. On day 28 the patient was taken off medication and the event resolved. On day 29 the patient was discharged from hospital and subsequently resumed medication. However, confusion reappeared on day 32. The initial event was misclassified in the clinical study report as "mental impairment" but has since been corrected in an erratum published in the same journal that published the original trial manuscript (Gravenstein 2013; Peters 2001).

Table 15. Psychiatric adverse events in oseltamivir prophylaxis trials
  1. Of the 66 events, 12 were classified as severe intensity (10 oseltamivir, 2 placebo)

 Oseltamivir Placebo Total 
Event type# Events%# Events%# Events%
Confusion50.2510.0760.17
Depression140.760.42200.58
Hallucinations20.100.0020.06
Anxiety70.3580.56150.44
Psychosis20.110.0730.09
Schizophrenia10.0500.0010.03
Bipolar disorder0010.0710.03
Sleeping disorder20.100.0020.06
Aggression10.0500.0010.03
Stress symptoms30.1500.0030.09
Restlessness10.0500.0010.03
Nervousness10.0500.0010.03
Suicide ideation10.0500.0010.03
Paranoia10.0500.0010.03
Alcohol related60.320.1480.23
Total472.35191.32661.92
Renal effects

There was a non-significant increase in renal events on-treatment (RR 3.17, 95% CI 0.96 to 10.49, I2 statistic = 0; RD 0.67%, 95% CI -2.93 to 0.01; NNTH = 150, 95% CI NNTH 35 to ∞ to NNTB > 1000) (Analysis 2.38). However, in sensitivity analysis using Peto's method the result for renal events was statistically significant (P = 0.02).

Zanamivir
Serious adverse events

There was no significant effect on serious adverse events in adult treatment trials (RR 0.86, 95% CI 0.49 to 1.50, I2 statistic = 0%) (Analysis 3.11).

Nausea, vomiting and diarrhoea

In treatment trials, there was no significant effect on diarrhoea in adults (RR 0.87, 95% CI 0.66 to 1.14, I2 statistic = 5%) (Analysis 3.33) or headache (RR 0.84, 95% CI 0.60 to 1.18, I2 statistic = 0) (Analysis 3.35). However, during the on-treatment phase, nausea and vomiting were significantly less frequent in the zanamivir arm (RR 0.60, 95% CI 0.39 to 0.94, I2 statistic = 0%; RD 1.63%, 95% CI 0.24 to 2.48%; NNTB = 62, 95% CI 41 to 411) (Analysis 3.32).

Renal, psychiatric and other harms

There was no significant effect observed on the renal system (RR 0.84, 95% CI 0.41 to 1.72, I2 statistic = 0%) (Analysis 3.45), or the psychiatric system (RR 1.16, 95% CI 0.57 to 2.38, I2 statistic = 0%) (Analysis 3.48). In adult treatment trials of zanamivir, there was no significantly increased risk of any other reported adverse events and there was no significant increase in adverse effects observed in prophylaxis trials, including psychiatric (Analysis 4.29) and renal effects (Analysis 4.30) on-treatment. There was no significant increase in harms associated with zanamivir treatment of children but data were sparse.

Effect on antibodies

There was no significant effect of zanamivir treatment on influenza diagnosis (Analysis 3.8) or probability of a four-fold increase in antibody titre (Analysis 3.9; Analysis 3.10).

Deaths

In oseltamivir treatment trials, there was one death overall. This event occurred due to acute respiratory syndrome in a placebo patient without influenza in study WV15812/WV15872. In prophylaxis trials, there were four deaths in total, all in elderly patients, with two in the placebo group and two in the oseltamivir group. Causes of death were reported as two cancers, one myocardial infarction and one intestinal perforation. However, for both deaths in the oseltamivir arms the participants experienced acute renal failure on-treatment prior to death.

There were eight deaths in total in the zanamivir trials. Six of the deaths were caused by neoplasias or cardiovascular events in elderly patients with multiple pathologies. However, two deaths were reported as due to influenza A pneumonia. One participant was on inhaled rimantadine plus placebo and the other on zanamivir.

The results of post-protocol hypotheses are in Appendix 10.

Discussion

Oseltamivir and zanamivir have small, non-specific effects on reducing time to alleviation of influenza-like illness symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether complications of influenza such as pneumonia are reduced, because of a lack of diagnostic definitions. Use of oseltamivir increases the risk of adverse effects such as nausea, vomiting, psychiatric effects and renal events in adults and the risk of vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence.

Reconstructing trial lists and indexing regulatory comments

Calls for incorporating unpublished data to supplement published trial data in systematic reviews and meta-analyses highlight deficiencies in the current methods for obtaining the most complete understanding of a drug's effects (Godlee 2010). Our methodological approach entailed comprehensive searching of unpublished sources, with a particular emphasis on obtaining unpublished and internal reports from drug manufacturers intended for regulatory submission and comments from national regulatory bodies. Our decision not to use published evidence as a basis for trial appraisal and data extraction meant that we had to reconcile and synthesise information from multiple unpublished sources. We had to devise a new method of searching, indexing, retrieving and reviewing trial data and to combine this understanding with regulatory comments to produce an informative review. The first step in this process entailed the need to develop our own reconstruction of the trial programme without initial help from outside sources. The reconstructed list of trials and then programmes took a whole-time-equivalent (WTE) researcher 20 days to compile. Due to the complexity of the task we suggest that in the future some of the essential phases, such as trial ID checking, be conducted in pairs.

One of the comments received on our protocol suggested that discrepancies between published and unpublished versions of the same data set could be due to mistakes in the non-peer reviewed, unedited clinical study reports (which may be corrected by the time of publication). Our experience, especially with the non-reporting of serious adverse events, points to the opposite being the case (Jefferson 2011b). Considering the fact that unintentional errors can occur, we believe the response should not be a resort to published papers as 'most accurate' and best unit of analysis, but rather that clinical study reports - as by far the most comprehensive record of a trial - remain the key unit of analysis, with the expectation that they be amended and kept as accurate as possible over time, with complete documentation of reasons for any amendments. We believed that the results of our review would be undermined without accessing a more complete body of evidence that we knew to be outside the public domain.

In theory, trial registers would be expected to provide a comprehensive picture of a drug's trial programme. However, registers were not our primary instruments to reconstruct zanamivir and oseltamivir trial programmes. Both drugs' programmes were mainly run in the late 1990s, before trial registration became the norm. In addition, registers may suffer from some of the problems that we were trying to address. Bourgeois 2011 audited entries for 546 trials of five major classes of drugs on ClinicalTrials.gov, the biggest prospective register of clinical trials, and found evidence of risk of reporting bias and delay in reporting of results. Another review of 152 trials found that the description of 123 (or 81%) of the trials in the sample had been changed in at least one key element in the time between registration and publication. The most frequent changes regarded outcomes (Huic 2011). Despite the current limits of registers, both specifically to this review and in the way they are run and updated, we believe that registers are an obvious first choice to start reconstruction of trials programmes. Searching for unpublished material has not yet become standard practice in conducting Cochrane reviews (Van Driel 2009), and is currently variably reported (Ghersi 2010).

The indexing and review of regulatory files was also a very laborious task. It took a WTE researcher three days to review the US Food and Drug Administration (FDA) regulator's comments and gain a basic understanding of the content. Four additional days were needed to read and annotate the FDA zanamivir files and 28 days for reading and annotating the oseltamivir files and building the Table of Contents-Evidence (TOCE). The exercise had to be repeated several times to cross-check content and expand annotations. Construction of the Table of Contents (TOC) was laborious. A first attempt at electronic mapping the TOC content took 12 and 8 hours respectively for the FDA and National Institute for Health and Clinical Excellence (NICE) regulatory documents. This was carried out using the Adobe Acrobat Optical Character Recognition (OCR) search facility, which enabled mapping of citation counts by document and by trial ID. Initially we used the trial prefix followed by the serial number ('WV15670') as ID. This procedure, however, had one major drawback linked to the nature of regulatory documents. As regulatory documents consist of notes, correspondence and reviews, the same trial is cited in a non-standardised way. For example, trial WV15670 is cited as 'WV15670' 15 times, as 'WV_15670' 12 times and simply as '15670' 19 times). Thorough searches must be conducted using all the different terms. As this can be very time-consuming, we decided to compare an Acrobat search with a Boolean string strategy containing all possible citation formats (for example, WV15758 OR WV 15758 OR Trial 15758 OR Trial15758 OR Trials 15758 OR Trials15758 OR 15758 OR study 15758 OR study15758) (this is logically equivalent to 'WV 15758 OR WV 15758') with a term-by-term search (i.e. separately searching for WV15758 and then for WV 15758 and so on). We reasoned that if the yield were comparable, the Boolean strategy would have been faster. The yield of citations of the two strategies was the same for six of seven 'tracker' studies but use of a Boolean string was considerably faster (an average of 3 versus 14 hours) than the term-by-term strategy. The National Institute of Clinical Excellence (NICE) submission citations took two hours to list in a TOC using a Boolean strategy. We adopted the Boolean search strategy to construct our TOC. Ultimately it is possible that a search with the trial numerals ('15670') may be sufficient to identify the vast majority of citations. To validate this method of searching further our methods should be repeated on other sets of regulatory documents.

Once we had reconstructed the trial programmes we submitted the results to GlaxoSmithKline (GSK) and Roche for their input. We received detailed feedback from both but as late as 2011 Roche's list of trials was incomplete. Despite the laboriousness of the methods, we believe we ended up with a far more comprehensive and less biased set of evidence than that available through the current system of journal-based publications. This shift in our data synthesis paradigm was made necessary by the numerous and documented discrepancies between regulatory and published evidence and by the sizeable risk of publication bias of the oseltamivir trial programme. The importance of reconstructing the trial programme by first generating a complete trial list was further reinforced upon discovering bias and oversights in regulators' handling of the trial programme. Regulators focus on a few mutually agreed "pivotal" trials whose data analyses are replicated by the FDA but not by the European Medicines Agency (EMA). Both largely ignored trial M76001, the largest oseltamivir treatment trial conducted prior to initial registration of the drug (and still unpublished). While the manufacturer may not have offered it as a "pivotal" trial, far smaller and even ongoing studies were included in the evidence base to support Roche's year 1999 New Drug Application number 021087 (Treatment of uncomplicated acute illness due to influenza infections in adults who have been symptomatic for no more than two days). The depth of the EMA scrutiny is harder to assess as we could find no reports of trial site visits or of data analysis replication, but we identified a pooled analysis of treatment trials, very similar to the Kaiser 2003 analysis which formed the basis for the EMA conclusion that oseltamivir affected complications reported, for example, on EMA's 4 October 2012 Summary of product characteristics (SmPC) (http://www.bmj.com/tamiflu/ema). We requested Modules 3, 4 and 5 (individual listings, demographic data and the statistical analysis report) from the EMA. However, for most oseltamivir trials, the EMA do not have the relevant documents and neither apparently do National Competent Authorities (email from the EMA, 24 May 2011; email from Dutch regulator MEB, 20 July 2011). This means that the Modules do not appear to have been either submitted to or requested by regulators, raising questions as to the extent of scrutiny of the clinical trials during the regulatory review of oseltamivir in Europe.

Our new method

Reviewing huge quantities of complicated data and linked comments is a very difficult and delicate process. The main problem is not so much the appraisal following standard rules and possible synthesis of data (as when we review published information), but the reconstructions and logical threading of a trial programme generating huge amounts of data needing appraisal. Also the manufacturer's full regulatory submission, which may have even more information than a full clinical study report, remains confidential. Most of the essential data required are available in clinical study reports, together with masses of less important data, but as we have explained even in this case there may be important omissions, such as mislaid diary cards for follow-up. Manufacturers are under obligation to provide regulators with all data requested to enable them to reach a decision: in doing so they produce vast submissions. None of the authors (all experienced systematic reviewers) had any experience of reviewing regulatory information. Given the laborious and painstaking process we tried to identify a quicker and equally reliable way of reviewing regulatory information but could not find any obvious shortcuts. However, we believe that providing a critical overview of a trial programme rather than minute dissection of each trial is necessary. This can be done by identifying the important topics in the trial programme (such as the effects of the drug on symptoms, infection, complications, transmission and well-being) and following them throughout the programme, knitting the evidence into a coherent narrative. This includes carrying out a high-level overview of the mode of action of the drug in different populations for different indications. Understanding any drug's mode of action is core to correct reporting of its strengths and limitations. In addition, a large part of the regulatory submission is made up of chemistry, microbiological, animal model pharmacodynamic and pharmacokinetic studies, which are important for shedding light on the trial programme but which seldom feature in systematic reviews. We are unsure as to whether this information could be considered as core information but an exhaustive review of a trial programme should include reviews dedicated to such topics.

These methods were crucial in discovering major concerns in trial conduct and validity, including the lack of comparability between arms induced by subset analysis and by the randomisation-analysis fork, high positivity rate of influenza, high gastrointestinal events in the placebo arms, possibly active placebo content and possible procedural breaches several trials, which are concerning. Overall, the safest and more conservative option appears to carry out analyses on the basis of the intention-to-treat (ITT) population, in which units of randomisation and analysis are the same and many of the potential problems listed are either not present or minimised.

Our novel methodology remains a work in progress.

Regulatory comments

Reviewing regulatory comments was an essential way to deepen our understanding of the trial programme. From early on in our review we hoped that a close reading of regulatory material would allow us to understand the reason for discrepancies between US and European regulators' conclusions regarding the effects of oseltamivir, particularly (but not limited to) their purported effect on complications (Doshi 2009). We were interested in what led the FDA to have far more cautious and conservative statements - as witnessed in the Tamiflu product label and FDA letters - in comparison to European regulators. Our access to huge amounts of FDA regulatory data allowed for many insights but gave us little visibility of manufacturers' responses. 

Some of the statements made by the manufacturer in the clinical study reports, and subsequently in contemporaneous publications and advertisements, appeared unsupported by the evidence provided at the time. The FDA drug regulatory reviewers' comments, although laborious to summarise and contextualise (because of the non-availability of the whole pharmaceutical submission), were confirmed by our reading of the clinical study reports. However, we were unable to find a statement explaining how the FDA reviewed each New Drug Application (NDA). FDA reviewing methods appeared to be a mixture of spot checks, re-run of statistical analyses and on-site inspections. An FDA methods volume or standard operational procedure may be among the documents not available from the web but accessible through a Freedom of Information (FOI) request. Neither the FDA nor the EMA have inventories of held documents, making it very difficult to know what to ask for under FOI rules. We concentrated on downloading or asking for specific clinical study reports and related documents or reviewers' comments on a particular NDA. The quantity of information held by regulators is likely to be large. For example, New Drug Application 21-246, the use of Tamiflu in the treatment of influenza in children submitted to the FDA on 15 June 2000 consisted of 137 volumes of study documents and possibly several electronic files. Although we do not know exactly how long a volume was, we have seen references to up to hundreds of pages in each volume.

Requesting specific documents and packages of information is especially important to allow a more efficient and timely reviewing process when confronted with a large volume of evidence, most of which could be of peripheral value. A request for a specific document is likely to be dealt with far more efficiently than a generic request for "all documentation relating to oseltamivir". This is one of the reasons why developing a TOC for any drug or family of drugs (no matter how time-consuming) is an absolute prerequisite for any serious attempt at reviewing regulatory evidence. This introduces another very difficult problem: how to handle huge quantities of structured information and the ethics of drawing conclusions from what is still a fragmentary (albeit sizeable) evidence base.

Overall the FDA assessment of the performance of oseltamivir was "modest". This adjective appears six times in a 50-page review document (FDA 1999c). For example, in the Division Director Memorandum dated 25 October 1999, under the heading "Public health role of antiviral treatment" the FDA states: "The clinical relevance of the modest treatment benefit is a highly subjective question" (FDA 1999c, PDF page 3). The FDA refused to accept claims of oseltamivir's effects on influenza complications as "false or misleading" statements in promotional materials (FDA 2000f). An FDA warning letter seems to imply, for example, that oseltamivir's mode of action is "proposed" or "possibly" [that proposed by the manufacturers] i.e. not certain (FDA 2000f). However, FDA reviewers appear to have missed important problems in Roche's clinical trials (such as the imbalance in the numbers of individuals classified as influenza-infected in oseltamivir treatment trials). Most of all, no one seems to have questioned the coherence of the evidence with the proposed mode of action of the drug.

Summary of main results

For the first time a Cochrane review is based on all relevant full clinical study reports of a class of drugs integrated by regulatory comments. Also for the first time, all clinical study reports of trials in a manufacturer's programme (regardless of their relevance to the review) are available to readers without any restriction (apart from minimal redactions to protect anonymity further). The role of Roche and GSK in making this possible should be recognised, as well as that of the BMJ, which kept the issue in the public eye until it was resolved.

The evidence we have presented and synthesised shows that both neuraminidase inhibitors (NIs) in this review have symptom-relieving effects, especially for self reported outcomes. They appear to have symptom-relieving properties that make people with influenza-like illness and self reported, investigator-mediated, unverified pneumonia feel better by shortening symptom duration and reducing the frequency of symptoms such as cough. For oseltamivir, this effect perhaps extends to cardiac symptoms, despite the short duration of treatment (five days). We are unsure what to make of this finding but we think it deserves further investigation.

The issue which triggered our change of evidence-seeking methods is partly resolved: no definitions of secondary illnesses were given anywhere in the clinical study reports (for example "pneumonia" was defined as "pneumonia" in the case report forms (Table 1) and diagnostic criteria were not given); clinical diagnosis in the absence of criteria and without X-ray has only a moderate chance of being correct.

We could not decide the level of diagnostic ascertainment of diagnosis of pneumonia and other complications, as it is unclear from the clinical study reports. Definitions of pneumonia were not given and the algorithm for classification of an event as pneumonia was not supplied. In oseltamivir trials, the case report form trigger for recording of adverse events and secondary illness was a question to the participant posed by the investigator. A typical phrasing is as follows: "Secondary illness reminder: Has the patient reported any sinusitis, otitis, bronchitis, other chest infection or pneumonia since baseline?" This was followed by a yes/no box to be ticked and an additional form was to be filled out by the investigator for collecting details on the secondary illness. A record of medications outside trial allocation was elicited in addition to the participant's diary card. The original and Medical Dictionary for Regulatory Activities (MedDRA) terms suggest diagnoses for all secondary illnesses and adverse events but there is no indication how the original and preferred terms were assigned. We therefore considered these outcomes to be "self reported, investigator-mediated, unverified" outcomes. For a subset of trials, secondary/intercurrent illness and adverse event data were collected on a single, one-page form. In our meta-analyses, we called this sub-analysis "Trials which collected data on non-specific adverse events or secondary/intercurrent illness form". For a different subset of trials, case report forms contained space to record diagnostic tests such as chest X-rays, tympanometry and sinus X-rays for all secondary illness but there was no reporting of such variables in the clinical study reports (Figure 12; Figure 13; Figure 14; Figure 15). In our meta-analyses, we called this sub-analysis "Trials which collected data on specific 'Diagnosis of Secondary Illness' form". None of the complications were defined as primary outcomes in any trial, which may explain the poverty of data definition.

Figure 12.

Sample "Adverse event or intercurrent illness" form (oseltamivir study M76001)

Figure 13.

Sample "Secondary illness" form (oseltamivir study WV15670)

Figure 14.

Sample "Diagnosis of secondary illness" form, page 1/2 (oseltamivir study WV15978)

Figure 15.

Sample "Diagnosis of secondary illness" form, page 2/2 (oseltamivir study WV15978)

In meta-regression of all 32 included studies that reported on "pneumonia", we found evidence that treatment effects for pneumonia are statistically different depending on the method of diagnosis. Unclear objective diagnosis was associated with an apparent 46% reduction in pneumonia due to treatment with neuraminidase inhibitors, whereas the use of objective criteria in the data collection showed no evidence of effect, with a risk ratio (RR) of 1.0. Age group (adults versus children), drug (oseltamivir versus zanamivir) and indication (treatment versus prophylaxis) showed no evidence of association with treatment effect.

Meaningful conclusions on the effect of either NI on complications of influenza are difficult to draw based on the trial evidence. In part this was due to the lack of standardised definitions. In addition, meta-analyses of these outcomes that lacked definitions were based on few events and therefore not robust. Caution is therefore urged in interpreting the meta-analysis result, which suggests that 100 patients (67 to 451) need to be treated with oseltamivir for one less self reported, investigator-mediated, unverified pneumonia. The same applies to the zanamivir treatment result, which suggests a reduced risk of self reported, investigator-mediated, unverified bronchitis in adults (number needed to treat to benefit (NNTB) 56, 95% confidence interval (CI) 36 to 155). The evidence suggested oseltamivir had a similar effect, although the result was non-significant.

As stated above, there is no evidence that definitions of complications in either paediatric, elderly or adult trials were ever prepared and incorporated in the trials' design. Therefore, the reporting of cases of 'otitis media', 'pneumonia', 'sinusitis' or 'bronchitis' are of unclear significance and importance, making it impossible to attribute a cause and draw conclusions (FDA 2000d). This is probably why the US Food and Drug Administration (FDA)-approved oseltamivir package insert, since 17 November 2000, has consistently stated: "serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. TAMIFLU has not been shown to prevent such complications." The original product label did not contain such a statement but on 14 April 2000, after oseltamivir was approved for sale in the United States, the FDA sent Roche an untitled letter about "Misleading Efficacy Claims" that the FDA had noted in Roche's promotional materials (FDA 2000a, PDF page 3). One of the statements that Roche made was: "Tamiflu reduces incidence of secondary complications (i.e. bacterial infections) by 45%." The FDA commented: "Further, you have claimed reductions in severity and incidence of secondary infections with Tamiflu that are misleading because they are not supported by substantial evidence" (FDA 2000a, PDF page 3). We do not know how Roche responded to the FDA but in subsequently available Roche promotional material information, Roche's statements were consistent with the FDA's demands (Doshi 2009).

There is uncertainty in the "complications" and "secondary illnesses" outcome definition therefore we carried out an analysis on the data from adult treatment trials on those complications classified as serious or those which led to study withdrawal. For oseltamivir, there was no evidence that treatment affected such complications (risk difference (RD) 0.07%, 95% CI -0.78 to 0.44) (Analysis 1.20; Analysis 1.55). This outcome could not be assessed in oseltamivir prophylaxis due to an insufficient number of events. For zanamivir, there was no significant evidence of a treatment effect on such complications (RD -0.04%, 95% CI -0.64 to 0.24) (Analysis 3.7; Analysis 4.8). This outcome could not be assessed in children due to an insufficient number of events.

Contrary to the FDA, the European Medicines Agency (EMA)'s oseltamivir 'Summary of Product Characteristics' states that oseltamivir significantly reduces the incidence of "specified lower respiratory tract complications (mainly bronchitis) treated with antibiotics" in individuals of 13 years of age and older. This claim is based on "a pooled analysis of all influenza-positive adults and adolescents (N = 2413) enrolled into treatment studies", of which 1063 were in the placebo group and 1350 were in the oseltamivir-treated population (EMA 2010). This statement appears in the EMA files as early as 2001 (EMEA 2001). These exact denominators appear in the Kaiser 2003 meta-analysis.

The design of the trials, as defined in the protocol with amendments, statistical analysis plan and case report forms, does not allow any further inferences. The effect on outcomes that were originally considered of secondary or tertiary importance (such as bronchitis and pneumonia) would have been clarified with better clinical definitions and investigations, as some of the serious adverse events were. These benefited from a paragraph-length narrative, which reported most of the salient features of the event.

Our previous decision to analyse the effects of oseltamivir and zanamivir on the ITT population has been confirmed for oseltamivir with the demonstration of the effect on antibody responses in participants in treatment trials, although no such effect is discernible for zanamivir. This effect leads to the introduction of selection bias with a significantly reduced probability of being diagnosed with influenza and an imbalance in the two arms if the intention-to-treat-influenza-infected (ITTI) population is analysed. The effect of oseltamivir on antibodies appears to be carried over to children with influenza-like illness. Its finding contradicts statements made by the manufacturer.

The seeming incomparability between arms of the influenza-infected subpopulations in the oseltamivir trials raises the question of how an appropriate analysis should be conducted. If influenza-infected groups are comparable (as appears to be the case in zanamivir treatment trials) then an appropriate analysis strategy (based on Senn 2004) would be to determine first the effect of treatment in the ITT population. If there is evidence of a treatment effect, then treatment by infected status interaction could be tested. If there was evidence of an interaction, then estimates of treatment effect could be derived separately for the influenza-infected and non-influenza-infected subpopulations. However, this analysis should be conducted on the ITT population using a single appropriate statistical model, obviating the need to conduct separate analysis on the influenza-infected subpopulation. Roche used geometric mean titres indicating antibody responses in the ITTI population to support their statement that oseltamivir does not affect antibody responses (for example, in Table 16 and linked text of Module 1 of trial WV15799). However, the use of such measures can be misleading. What are required for such an analysis are data on how many ITT population participants responded by arm, at what level of antibody response and how many were tested. Such data could not be identified with certainty. A further effect of choosing a subpopulation analysis (ITTI in treatment trials and ITTIINAB (ITT influenza-infected index cases who had negative virology at baseline) in prophylaxis trials) as the primary analysis is the restriction of the generalisability of results. This is especially so in the case of design flaws (for example, in the case of the post-exposure prophylaxis trial WV15799, where all index cases were not treated and around 55% of participants were dropped from the ITTIINAB analysis). In this cluster-trial design households should be included as random-effects in the analysis to take account of within-household correlations.

Table 16. Proportions of contacts with positive serology data (WV15799 ITTIINAB population)
  1. ITTIINAB population: ITT influenza-infected index cases who had negative virology at baseline

    Chi² P = 0.001

Positive

serology

Group Total

Placebo

N

%

Tamiflu

N

%

No166
83.0
192
93.7
358
 
Yes34
17.0
13
6.3
47
 
Total200205405

A significant but slight reduction of the proportion with serum antibody (mostly haemagglutination inhibition (HAI) antibody) titre rise by four-fold or more among those who were tested was shown in this review. This was consistent with the evidence from animal tests using a sub-clinical dose of oseltamivir in influenza A/H1N1-infected mice (Takahashi 2010). Takahashi 2010 reported a non-significant slight reduction of haemagglutinin (HA) specific IgG antibody in serum and spleen, while they reported about an 80% significant reduction of HA specific secretory IgA antibody (s-IgA Ab) in nasal wash and bronchoalveolar fluids (BALF) on day 12. From this evidence, they warned that the risk of re-infection may increase in patients showing a low mucosal IgA antibody response following oseltamivir administration. These experiments were done because they had the unexpected finding that paediatric influenza patients treated orally with oseltamivir for five days had significantly low levels (about 60% reduction on day five) of anti-influenza S-IgA nasopharyngeal fluids compared to levels in patients not treated with oseltamivir (Sawabuchi 2009). Their findings are consistent with our findings that serum HA inhibition (HAI) antibody response was decreased by oseltamivir administration, though s-IgG Ab could not be analysed in our study because the data were not reported in the clinical study reports (Sawabuchi 2009; Takahashi 2010). These findings are also consistent with the evidence on the mode of action of oseltamivir from animal models (Module 2 of Mendel 1998; WV15670; WV15671) and from viral challenge, randomised, placebo-controlled studies in humans (Hayden 1999).

Pro-inflammatory cytokines, including interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), were completely suppressed by oseltamivir administered 28 hours after the experimental inoculation of influenza virus, while the reduction of viral titre in nasal lavages was partial (Hayden 1999).

There is decisive evidence that administration of oseltamivir in animals challenged by respiratory syncytial virus (RSV) that lacks a neuraminidase gene showed a symptom-relieving effect (decreased weight loss) and inhibition of viral clearance (Moore 2007). These effects were accompanied by a decreased CD+8 T cell surface sialoglycosphingolipid GM1 level, which is regulated by the endogenous sialidase/neuraminidase in response to viral challenge along with suppression of cytokine expression (Moore 2007). They are consistent with those findings from the pharmaceutical company and their investigators. The findings of the study by Moore 2007 suggest a risk of infection and exacerbation of infection by pathogens other than influenza virus in spite of the apparent reduction of symptoms from infection.

Sufficient plasma concentration of oseltamivir carboxylate from orally administered oseltamivir phosphate may act directly on the host endogenous neuraminidase to reduce (or suppress) the immune response even at the dose of 20 mg twice a day for five days. However, the bioavailability of inhaled zanamivir seems to be very broad: about 10% to 70%, as estimated by the area under the curve (AUC) data from the inhalation and intravenous study from the Japanese Summary Basis of Approval (JSBA). The difference in peak concentration (Cmax) was much larger (6 to 37-fold). This means that inhaled zanamivir could reach a high enough concentration to reduce the immune response, if it is administered at a high dose or a for long period, or if the patient is very susceptible. In fact, a double-blind, placebo-controlled trial using healthy volunteers to investigate the effect of zanamivir treatment (20 mg/day for 14 days) on the humoral immune response to influenza vaccine showed that the zanamivir group responded with significantly lower antibody titres to the H1N1 (Cox 2001). Pro-inflammatory cytokines, including IL-6, TNF-α, IFN-γ and other chemokines, were almost completely suppressed in the viral challenge randomised controlled trial (RCT) using a very high dose (600 mg) of intravenous zanamivir before inoculation of the influenza virus in human adults (Fritz 1999).

These findings all suggest that the low immune response, with a low level of pro-inflammatory cytokines, induced by the action of oseltamivir carboxylate may reduce the symptoms of influenza irrespective of an inhibition of influenza virus replication, which is widely believed to be the main mode of action of NIs.

In addition, the potential hypothermic or antipyretic effect of oseltamivir (but not zanamivir) as a central nervous system depressant may also contribute to the apparent reduction of host symptoms (Ono 2008; Ono 2013).

Zanamivir had no effect on pneumonia symptoms in treatment trials, even when the diagnosis was supported by a chest X-ray; nor did it affect antibody responses, but it did affect bronchitis. We think that this shows an undeniable symptom-relieving effect of both drugs, which also applies to more severe, if undefined, syndromes. Both drugs relieve influenza-like illness symptoms by around 0.6 to 0.7 of a day, although this is first relief and not necessarily complete relief. In the case of oseltamivir, the mix up with the follow-up cards does not allow us to draw any conclusions on a possible length of the duration of symptom relief. Also of note is the fact that this important information came to light from the FDA reports and not from the clinical study reports of the relevant trials (WV15670; WV15671). This points to the incomplete nature of reporting in the clinical study reports and the important role of Summary Basis of Approval (SBA) regulatory information.

In a subgroup analysis we found no evidence of a difference in treatment effect for zanamivir on time to first alleviation of symptoms in adults in the influenza-infected and non-influenza-infected subgroups. Both subgroups showed strong evidence of treatment effect of 0.5 to 0.7 days reduction in time to first alleviation of symptoms. This strongly supports our hypothesis that these drugs do not have an influenza-specific effect.

Oseltamivir relieves symptoms in otherwise healthy children, but no effect was noted with zanamivir, which may be due to the limited power of the two eligible trials with just over 700 children in total. However, oseltamivir does not have any effect on asthmatic children with influenza-like illness, a population which should benefit most from its use. One explanation for this finding is in the nature of the young asthmatic population, which is well cared for and used to regular powerful medications and close follow-up. The incremental benefit of oseltamivir is thus likely to be undetectable in such a population. An alternative explanation could be the higher susceptibility of the immune system to suppression by oseltamivir carboxylate in asthmatic children compared with those in the placebo group. The finding that oseltamivir administered to asthmatic children reduces symptoms faster than in placebo recipients at the beginning of the study, but during the off-treatment period more recovered later than those administered placebo, gives some support to this explanation.

There is no evidence of an effect of oseltamivir on hospitalisations. Hospitalisations are an important but poorly defined outcome in the oseltamivir protocols, inconsistently reported in the clinical study reports and overlooked in the zanamivir protocols and reports.

The oseltamivir trials did not detect any influenza-related deaths, reflecting the relatively benign nature of influenza in the study populations. The zanamivir trials detected eight deaths, of which only two were likely to be due to influenza and both occurred in the intervention arms. All the trials were likely to be underpowered to detect differential effects on mortality, but the absence of deaths in placebo recipients again underlines the benign nature of influenza. In fact mortality in Japan during the 2009A/H1N1 influenza outbreak was 198 among about 20 million influenza patients (one in 100,000 infected). Early deterioration leading to death was observed more frequently in oseltamivir compared to zanamivir or no antivirals recipients (Hama 2011).

Overall the two drugs have similar benefits but quite different toxicity profiles.

On average, for every 28 (14 to 112) adults treated with oseltamivir there will be one more report of nausea and for every 22 (14 to 42) adults and 19 (10 to 57) children there will be one more report of vomiting. Oseltamivir seems to have an apparent protective effect on diarrhoea, contrary to the other evidence of gastrointestinal disturbance. This finding might be as an effect of a placebo containing dehydrocholic acid or it might be one of the results of the influenza-like illness symptom-relieving effects (similar to relief of tachycardia and palpitation). The other apparent gastrointestinal events, such as nausea and vomiting, may be the results of central nervous disorders indicated by "only day 1 increase of vomiting" in treatment trials in children.

For every 62 (41 to 411) adults exposed to zanamivir there will be one less case of nausea and vomiting, but no such effect was visible in children, probably because of a lack of power. Zanamivir does not appear to affect the frequency of bowel movements.

In the prophylaxis data set, "influenza without laboratory confirmation" (i.e. influenza-like illness) was only partially reported in the oseltamivir clinical study reports and not reported in the zanamivir clinical study reports, except for NAI30034 in which no significant reduction was observed (9% versus 10%). As a consequence we are unable to report on that outcome. The size of the reduction in influenza symptoms in oseltamivir prophylactic trials is inferior in magnitude to that seen in hand washing to prevent severe acute respiratory syndrome (SARS), based on seven case-control studies (odds ratio (OR) 0.77, 95% CI 0.70 to 0.84, I2 statistic = 68%, RD -0.12, -0.16 to 0.08, I2 statistic = 26%), the NNTB being approximately 50 for prophylaxis with oseltamivir and eight with hand washing (Jefferson 2011a).

There is a significant reduction in the proportion of patients with symptomatic influenza with both NIs. However, these findings do not reflect the true efficacy for prevention of influenza, because they conceal the positivity of laboratory testing (measured through tests of viral shedding and four-fold antibody titre rise).

We found an apparent prophylactic effect of zanamivir on pneumonia (which was not defined in case report forms) when it was used for 14 to 28 days. However, we found no evidence of significant effects on other complications and no evidence of an effect of oseltamivir on complications or hospitalisations.

Oseltamivir induced nausea in people undergoing prophylaxis but there was insufficient evidence to show an association with vomiting.

On-treatment renal adverse events were three times more common in the oseltamivir arms compared to the placebo arms, with 150 treated patients leading to one additional event. The two participants who died in the oseltamivir arms both experienced acute renal failure while on-treatment, although only one of those events was listed as an adverse event. The unlisted event was in a 91-year old female who was "withdrawn from the study on Study Day 15 because her estimated creatinine clearance was less than 30 mL/min. The screening laboratory examinations, that were carried out 10 days before the start of study treatment, were normal". Hyperglycaemic adverse events (aggravated diabetes mellitus or hyperglycaemia) were also more common in the oseltamivir arms, with eight events in total (one in WV15673/WV15697, two in WV15708 and five in WV15825) compared to none in the corresponding placebo arms. These data are only presented descriptively as they are too few (< 10) to meta-analyse formally, as prespecified in our analysis plan.

Finally, oseltamivir caused headaches and psychiatric harms in adult prophylaxis trials. Headaches are one of the most prominent harms of oseltamivir. There is evidence of a dose-response effect in prophylaxis trials WV15673/WV15697 (P = 0.013), in which headaches were observed in 202/519, 225/520 and 242/520 participants in the placebo, oseltamivir 75 mg once daily and 75 mg twice daily arms, respectively.

In the psychiatric category, several rare and severe single events (nervousness, aggression, hallucinations, psychosis, suicide ideation and paranoia) were reported significantly more frequently in the intervention arm. Added to other more frequently reported but not significantly different events (such as depression and confusion) this gave a large effect and a relatively small number needed to treat to harm of 94 (36 to 1538). The importance of such a finding lies in the distribution of oseltamivir to large numbers of asymptomatic individuals following pandemic plans. There were no prophylaxis trials in children that met our inclusion criteria, therefore we cannot report on prophylaxis harms in this important population.

The question of why oseltamivir treatment trials failed to identify a clear association between oseltamivir and psychiatric harms, although a weak dose-dependent association was observed, is a moot point. It is possible that influenza-like illness and influenza symptoms masked the harms in those who were already symptomatic and therefore recruited in the treatment trials (and influenza-type symptoms were excluded as adverse events to be reported). The reporting issue of compliharms may have helped to mask such events. Alternatively, it could be that these events are rare in the populations studied and that there was insufficient power to detect an association. The CI was wide (0.43 to 2.03) and does not rule out a doubling in risk due to treatment - as was found in the prophylaxis trials. It is also possible that the risk of psychiatric harm increases with increasing dose (as the data from trials WV15670 and WV15671 suggest) and increasing duration of treatment (as the prophylaxis trials suggest).

Toovey 2008 assessed the issue and failed to find an association between neurological and psychiatric adverse events and oseltamivir exposure. The outcomes studied were not based on the a priori definition of psychiatric adverse events as defined in the clinical study reports. The definition was constructed post hoc based on a selected group of adverse events taken from the psychiatric, neurological and injury body systems in the reports. The issues are described fully in Jones 2012 and Toovey's response is in Toovey 2012. Toovey 2008 reviewed only retrospective observational studies and did not review three prospective cohort studies conducted in Japan.

A meta-analysis of three prospective cohort studies of neuropsychiatric adverse events (NPAEs) in Japanese children show a pooled odds ratio for abnormal behaviours due to oseltamivir exposure of 1.55 (95% CI 1.21 to 1.98; P = 0.0005) without significant heterogeneity (Hama 2010). In one prospective study of several thousand children with influenza carried out to test the hypothesis of a causal relation between oseltamivir and neuropsychiatric events, abnormal behaviour was observed more frequently in oseltamivir recipient children than in controls (RR 1.57, 95% CI 1.34 to 1.83). Abnormal behaviour was observed in 3.4 per 100 person day (or 13.8%) in the oseltamivir group, compared to 2.2 per 100 person-days (or 8.8%) in the control group (Yorifuji 2009). Reanalysis of this study population, focusing on delirium and unconsciousness, also showed a significant association between oseltamivir and neuropsychiatric events, especially in the very early phase of the illness within a day of commencement of fever (Fuiita 2011). These indicate that prospective and intentional collection with this scale of participants may be necessary in treatment RCTs.

Animal toxicity study results firmly support the effect of oseltamivir on the central nervous system. One of these is the hypothermic effect of oseltamivir (but not zanamivir) administered orally, intraperitoneally (Ono 2008; Ono 2013) and intracerebroventricularly (Ono 2013). The other is that intra-duodenal or intravenous administration of oseltamivir to mature rats induced respiratory arrest shortly followed by cardiac arrest. These studies clearly show central depressant effects of oseltamivir (Kimura 2012). Moreover in the post-marketing toxicology phase studies by Roche, many symptoms that the manufacturer considered "item-related" were observed: alterations in respiration including decreased respiratory rate/gasping and altered mucous membrane/skin colour (pale) prior to death. Although the manufacturer denied the causality (Freichel 2009), symptoms at two hours after administration that showed dose-related increase were lack of olfactory orientation, lack of cliff aversion and low or very low arousal. Twenty-four of 52 pups that did not exhibit cliff aversion were later found dead. Fourteen of 17 animals with low or very low arousal died thereafter. These findings are consistent with the clinically observed psychiatric symptoms in the RCTs and post-marketing spontaneous reports.

Zanamivir was well tolerated. However, a potentially active placebo may have masked the occurrence of bronchospasm in zanamivir trials.

Treatment trials were mostly under-recruited and often their results pooled post hoc in two or even three trials, and yet they showed very high influenza positivity rates. One possible explanation for this lies in the intensive surveillance carried out in the predefined trial centre areas and the restricted time span of recruitment during high likelihood of positivity periods. This may be why many centres with low levels of recruitment are listed in the clinical study reports; this limits the generalisability of the results to everyday life.

In a primary or secondary prophylaxis indication the postulated central effect of oseltamivir is confined to suppressing symptoms, as infection was not prevented even when oseltamivir was administered prior to the inoculation of influenza virus both in animals (Mendel 1998) and in humans (Hayden 1999) and the prophylaxis trials. However, the central problem remains the incompatibility of the two contrasting claims of its activity against antibody production. If, as reported in many documents, oseltamivir does not interfere with antibody production (see, for example, FDA 2011a; Roche Investigators' Guide), how is it possible that oseltamivir prevents cases of influenza when part of the definition of prevented cases in oseltamivir trials was based on absence of antibody response?

The apparent ability of oseltamivir to interfere with antibody response calls into question the mode of action of the drug and puts in doubt the proposed effects of oseltamivir. One possibility in treatment trials is that oseltamivir administration, by interfering with antibody production, has the effect of selecting the strongest antibody responders in the ITTI subpopulation. These individuals are classified as influenza cases and are included in the oseltamivir arm of the ITTI population. This selected subpopulation probably represents the healthiest or those least likely to experience complications. An alternative consequence could be that interference with antibody production in the oseltamivir arm led to active arm participants being more likely to develop complications due to impaired immune function.

Evidence from prophylaxis and secondary prophylaxis trials suggests that in addition to the apparent similar mode of action as in the treatment studies, suppression of viral shedding in nasal swab may be of importance. In the former, participants who become positive (i.e. who are subsequently classified as cases of influenza) in the oseltamivir arms are the few who mount a strong response despite oseltamivir interference. The remainder (who are significantly more than in the placebo arm) are classified as prevented or avoided cases. However, as prophylaxis clinical study reports do not report antibody responses and viral isolate results for the ITT populations either, it is impossible to tell whether this proposed mode of action fits all the evidence. The effect of oseltamivir on nasal shedding is consistent with the proposed mode of action of NIs in preventing the virus from leaving the host respiratory epithelial cells, which are covered by a mucous layer. Compared with the rather small reduction of symptoms of influenza-like illness and reduction in antibody rise (up to 10%) by both oseltamivir and zanamivir, the extent of the reduction of symptomatic influenza is almost half. This may be due to reduction of influenza viruses in the nasal swab sample.

In prophylaxis there is no evidence that oseltamivir reduces symptomatic influenza-like illness. Oseltamivir reduces the number of prophylaxis participants testing positive (based on antibody rise and/or culture test). However, this finding is weakened by oseltamivir’s interference with the viral replication on the swab and effect on antibody production. In addition oseltamivir does not affect asymptomatic influenza and there is no evidence that it interferes with person-to-person spread.

Similarly to the FDA (FDA 1999c; FDA 2000c) because of the problems with the design of study WV15799 we could not draw any conclusions on the ability of oseltamivir to interrupt viral transmission.

This is important as the results of trial WV15799 formed part of the WHO3 rationale for use of the drug to interrupt transmission from person to person and allow time before the arrival of vaccines in the event of a pandemic furnishing a seemingly powerful rationale for stockpiling oseltamivir.

This shows the importance of availability of full clinical study reports, something the WHO did not have.

Antibody suppression seems stronger for oseltamivir than zanamivir, probably due to the difference in bioavailability. It may be that evidence of other effects, such as hyperglycaemia and renal impairment (though significance was marginal) in the prophylaxis trials may be due to inhibition of the host's endogenous neuraminidase, which impairs the cell function of various organs (Hama 2008). Overall, the significance of oseltamivir for nasal shedding is unclear but problems with sampling and culture undermine any claims as to its secondary prophylactic properties, as the FDA made clear in its response (FDA 1999c).

The dose-response increase in psychiatric events in the "pivotal" oseltamivir treatment trials and the increase in vomiting only on day one in treatment trials in children may be due to the sudden onset of the central action of unchanged oseltamivir (Hama 2008). Brain concentration of unchanged oseltamivir increases during the early phase of influenza in juvenile animals (Freichel 2009), due to a reduced or low function of p-glycoprotein, a major transporter of oseltamivir at the blood-brain barrier (Hama 2008; Kimura 2012). The likely centrally mediated mode of action of oseltamivir is supported by the finding of adverse events in healthy people in prophylaxis trials. However, these effects may also be derived from a delayed action associated with host endogenous neuraminidase inhibition by oseltamivir (Hama 2008), because this appeared after more than a week's exposure the drug and lasted for more than two weeks. Other effects, such as pain in the limbs, hyperglycaemia or diabetic events, reduction of antibody rise and reduction of cytokine induction, may also be due to the suppression of the host's endogenous neuraminidase by oseltamivir (Moore 2007). Pain in the limbs and metabolic control events (mainly hyperglycaemia) were in excess in the oseltamivir arms, but we did not carry out a formal meta-analysis, as they were not prespecified in our analysis plan and the number of events was below 10 for metabolic events.

Statements made about the capacity of oseltamivir to interrupt viral transmission and reduce complications are not supported by any data we have been able to access.

We have not reviewed other NIs, such as laninamivir and peramivir, or other antivirals, such as the adamantanes (amantadine and rimantadine), or antipyretic/anti-inflammatory agents either. Laninamivir and peramivir may be more potent as NIs, because their bioavailability is far higher than zanamivir and may affect the host's endogenous neuraminidase. Adamantanes are well known centrally active agents and may be more harmful than oseltamivir and zanamivir. Anti-inflammatory antipyretics (except paracetamol) may be more toxic than NIs (Hama 2008). Hence, the other NIs, adamantanes and anti-inflammatory antipyretics may not be alternatives to oseltamivir and zanamivir.

Overall completeness and applicability of evidence

We used the Cochrane seven-domain 'Risk of bias' instrument to assess bias. The availability of partial or complete clinical study reports decreased the uncertainty and allowed definitive judgements to be made. Previous unclear risk of bias became certainty of bias or certainty of absence of bias. Certainty or low levels of uncertainty are due to our expectations regarding the complete clinical study reports. We were expecting to have all relevant and consistent information available for our reviews, but when it was not, our judgements changed because we found gaps in the availability of information and inconsistent information. We are still uncertain whether the complete study reports represent an exhaustive and coherent source of trial narrative and data.

In the case of treatment trials, conclusions and generalisations are drawn from a subpopulation in which the two arms do not appear comparable due to the apparent ability of oseltamivir to interfere with influenza antibody production. The effect of oseltamivir on the gastrointestinal tract appears to be notable, although a definitive statement will only be possible once the mode of action and dosage of dibasic calcium phosphate dihydrate and dehydrocholic acid have been clarified. The high percentage of influenza infections appears to be in contrast with the need to pool or delay several trials and the small recruitment size of others because of a lack of influenza circulation. In the case of post-exposure prophylaxis trials, the selection of the infected population has the effect of excluding from the analysis large percentages (in some cases over 50%) of participants. This brings the generalisability of the results of these trials into question.

Much has been made in the trial programmes of viral nasal voidance as a marker of effect. However, its measurement was unreliable in treatment trials as this verbatim quote from the FDA review shows: "Duration of viral shedding was measured from treatment initiation to the time of the first negative virus culture with no subsequent positive cultures. Upon reviewing a list of viral shedding patterns provided by the applicant on 8/16/99, two problems emerged: (1) the pattern of virus shedding was fluctuating in at least 33 subjects (i.e. pos-neg-pos-neg, with or without a subsequent negative result). (2) In at least 100 subjects, the last virus shedding sample was the first negative sample in sequence, meaning there was not a subsequent negative confirmation. Given the fluctuating pattern of virus shedding, to estimate the duration of viral shedding based on the occurrence of a single first negative data poses a high level of uncertainty" (FDA 1999c).

In all programmes, the effect on complications was based on unclear and potentially unreliable definitions, often at the discretion of local clinicians and confirmation (e.g. radiological confirmation of pneumonia) was not consistently reported when it did occur. In the ITT population, the correct population for analysis, there is no credible effect of oseltamivir against pneumonia as the significance of the term "pneumonia" is not clarified.

In the case of post-exposure prophylaxis trial WV15799, nasal voidance was measured only in symptomatic subjects as an adjunct to protocol version H. However, this does not prevent the manufacturers from making claims of effect for all these outcomes.

Other general requirements, such as presentation within 36 to 48 hours, raise questions about the generalisability of the research evidence. However, underlying all our doubts is the conflicting evidence on the mode of action of the drug.

Most of the trials were substantially under-recruited and so had insufficient power individually to answer the research question.

Quality of the evidence

We assessed all full clinical study reports of relevant trials. An example of the kind of detail available in complete clinical study reports and the importance of the trial timeline in assessing the presence of bias is the observation that of the clinical study reports for the included trials, only one contained a protocol that predated the beginning of participant enrolment, only two had statistical analysis plans that clearly predated participant enrolment and three had clearly dated protocol amendments. No oseltamivir clinical study report included a clear date of unblinding.

All reports in our review were sponsored by the manufacturers. It is known that published studies sponsored by the pharmaceutical industry are more likely to have outcomes favouring the sponsor compared to studies which have other sponsors (Lexchin 2003; Lundh 2012). As the evidence relates to published studies, we do not know whether the findings are applicable to clinical study reports.

Potential biases in the review process

The main limitation of our study is our relative inexperience in dealing with large quantities of information and our lack of familiarity with certain trial documents, such as randomisation lists. Randomisation lists appeared to be of two types. The first was a pre-randomisation list of random codes with which participants' IDs cannot be matched with the participant IDs used within other sections of the clinical study report. The second was a post hoc randomisation list to which individual participants can be matched but the original generated codes are not shown. In both cases the truly random generation of the sequence could not be properly assessed because either the original codes are not provided or original codes cannot be matched to patients.

We have created methods and procedures to address the risk of reporting bias that we identified in published trials, but remain uncertain about the success of these new methods.

Agreements and disagreements with other studies or reviews

Several reviews of NIs are now available (Burch 2009; Cooper 2003; Falagas 2010; Tappenden 2009; Turner 2003), including several separate versions of our previous reviews (Jefferson 2006; Jefferson 2009a; Matheson 2007; Shun-Shin 2009). All are mainly based on published information and reach similar conclusions to our 2006 review, which sparked the reader's comment and subsequent investigation and change of methods.

Following publication of our review update in December 2009, Roche asked the Harvard-based academics Hernan and Lipsitch to repeat the Kaiser analysis to confirm or reject Kaiser's conclusions (Hernan 2011). They were not provided with any funding to carry out this analysis and Roche ultimately provided them with patient-level data sets and Module 1 for the 10 Kaiser trials and one more treatment trial (WV16277). An important methodological difference between Hernan and Lipsitch's analysis and that of Kaiser was Hernan and Lipsitch's decision to privilege a true ITT analysis over the sub-population analysis featured in the Kaiser analysis. Our Cochrane review also analyses the ITT population.

The Kaiser analysis concluded that oseltamivir provided two statistically significant reductions: in lower respiratory tract complications and in hospitalisations.

Hernan and Lipsitch evaluated lower respiratory tract complications and found a statistically significant, but smaller, reduction in the risk of these complications.

Hernan and Lipsitch omitted evaluating the Kaiser paper's conclusion that oseltamivir reduced the risk of hospitalisation. They wrote, "it was not possible to assess the potential benefit for high-risk participants who are hospitalised, because the sample size of most studies was too small to consider hospitalisation as an outcome."

Hernan and Lipsitch do not elaborate on or highlight their apparent methodological disagreement with the Kaiser 2003 analysis and it is not reflected in the news article published on the Harvard website entitled "Oseltamivir effect on complications confirmed by reanalysis" (http://ccdd.hsph.harvard.edu/NewsEvents/Oseltamivir-reanalysis). In fact, Hernan and Lipsitch did not confirm one of the key conclusions of the Kaiser paper (Kaiser 2003).

Unfortunately, the Hernan-Lipsitch analysis has been cited by influential bodies such as the European Centre for Disease Prevention and Control (ECDC) as "confirmation of the original Kaiser meta-analysis" (http://ecdc.europa.eu/en/activities/sciadvice/_layouts/forms/Review_DispForm.aspx?ID=561&List=a3216f4c%2Df040%2D4f51%2D9f77%2Da96046dbfd72) despite the fact that Hernan and Lipsitch did not confirm one of the key conclusions of the Kaiser paper (Kaiser 2003).

For complications, while Hernan and Lipsitch clearly produced similar results to Kaiser, we do not think that this means the result is more credible. In view of our findings, we suggest that these results should be interpreted with caution. We have published our preliminary comments (Cochrane Neuraminidase Inhibitors Review Team 2011). The approach Hernan and Lipsitch took in analysing data was insufficient to provide a credible, independent check on validity and reinforces the importance of detailed, critical assessment of entire trial programmes, with access to full-length study reports. Our analysis questions the coherence between the evidence and the proposed mode of action of oseltamivir.

The Ebell 2012 review concluded that there was "no evidence that oseltamivir reduces the likelihood of hospitalisation, pneumonia or the combined outcome of pneumonia, otitis media and sinusitis in the ITT population". This conclusion was based on Module 1 of the 10 Kaiser trials plus WV16277. These are the same 11 trials as Hernan 2011.

Authors' conclusions

Implications for practice

On the basis of the findings of this review, clinicians and healthcare policy-makers should urgently revise current recommendations for use of the neuraminidase inhibitors (NIs) for individuals with influenza. Our findings confirm that both oseltamivir and zanamivir reduce the time to symptomatic improvement in adults (but not asthmatic children) with influenza-like illness. The size of this effect is small, approximately half a day. It is unclear whether this is superior to treatment with commonly used antipyretic medications. However, we did not find any credible evidence that either oseltamivir or zanamivir reduce the risk of complications of influenza, particularly pneumonia, nor reduce risk of hospitalisation or death. Moreover, even in individuals at higher risk of complications, such as children with asthma or the elderly, we found no evidence of a beneficial effect for reducing risks of complications.

Based on these findings there appears to be no evidence for patients, clinicians or policy-makers to use these drugs to prevent serious outcomes, both in annual influenza and pandemic influenza outbreaks. Practice recommendations and drug labelling needs to be changed to reflect these findings.

When used as prophylactic agents to prevent the occurrence of influenza in individuals or families, our findings again suggest a minimal effect on prevention. Based on this, there is little support for their use as prophylactic agents, for example, during influenza epidemics. Given that oseltamivir is now recommended as an essential medicine for the treatment of seriously ill patients or those in higher-risk groups with influenza (H1N1 2009) (WHO 2013a; WHO 2013b), this is of some concern.

Reasons why prophylaxis treatment is not clinically meaningful include: 1) according to modelling studies, for prophylactic treatment to be effective, 80% of the population require at least eight weeks of treatment, which has not been trialled (Longini 2004); 2) models assume the relative risk reduction observed in low risk populations, transfers directly to populations at higher risk (i.e. an absolute treatment effect of 31%, approximately 15-fold higher than the absolute effects we observed in prophylaxis trials (Longini 2004); 3) A high proportion of people, at least two-thirds require recognisable influenza symptoms; 4) treatment has to be effective against both asymptomatic and symptomatic infections (which it is not), in modelling studies asymptomatic infections are assumed to be 50% as infectious as symptomatic infections (Longini 2004); 5) because the influenza season can last four to five months, any secondary strategy, such as vaccination, would have to be widely available at the end of the eight week treatment period, and 6) a full understanding of the effect of the treatment in prophylaxis is unknown because symptomatic influenza-like-illness without laboratory-confirmation was only fully reported in one study. This study (NAI30034) showed no difference in proportion of patients with symptomatic influenza-like-illness (with or without lab confirmation) (RR 0.90, 95% CI 0.73 to 1.11).

The small benefits we noted in symptomatic improvement and the lack of credible evidence for an effect on serious complications needs to be balanced with the adverse effects found with these drugs in meta-analyses, especially diabetic/hyperglycaemic, renal and neuropsychiatric effects in all those people for whom the World Health Organization (WHO) recommend use.

Our results do not discount the potential benefit of using zanamivir and oseltamivir in individuals under particular situations, for example in immunocompromised or in compassionate cases, where few other therapeutic options may exist. However, NIs themselves may be immunosuppressants. Our findings do not support the stockpiling of NIs, nor oseltamivir's inclusion in the WHO's list of essential drugs.

The rationale for undertaking the current review and the methods and pressures that needed to be employed to obtain and evaluate the evidence for these drugs has significant implications for the robustness of the scrutiny that new drugs undergo prior to entering widespread clinical use. We believe that several steps now need to be put in place to provide patients, clinicians and policy-makers with the most transparent assessment of the relative benefits and risks of new drugs.

First, our findings imply that numerous national and international bodies appear willing to accept biased or incomplete trial reports seemingly at face value. This ready willingness is in contrast with the considerable time and effort needed to change their recommendations. Second, published trials are unlikely to provide the level of detail to allow the results of a drug trial to be properly evaluated and risk presenting a partial and potentially biased report of trial conduct and findings. This has implications not only for the reporting of trials but also the weight that can be applied to published studies alone. Third, clinicians and policy-makers should be cautious in interpreting and using the findings of systematic reviews including only published studies, particularly those that comprise only a portion of an entire drug trial programme, or which contain only a portion of the results of trials. There have been many systematic reviews of NIs, none assessing the full trial programme or full trial results, thus limiting their validity. We suspect a similar situation exists for other drugs. Fourth, clinical policy-makers at the national and international level should raise the level of scrutiny needed in the cases of drugs that are likely to be used by large numbers of people who are either asymptomatic or have short, self limiting illnesses such as influenza ('public health drugs') and where the potential for benefit (and harm) is vital. Given the weight of these decisions (with serious implications for both correct and incorrect decisions), policy-makers should not face the barrier of being denied access to what sponsors regard as commercially sensitive information.

Without concerted efforts from multiple stakeholders to put the above measures in place, it is not possible to provide objective assessment of the benefits and risks of new drugs. This risks not only patients potentially missing out on effective treatments, but also patients being exposed to either ineffective (or harmful) treatments.

Implications for research

Our findings have implications for research on the mechanism of action of NIs, with special regard to any direct central action of oseltamivir and the inhibitory effect of the host endogenous neuraminidase of various organs and systems. We could not reach a consensus on whether further trials are warranted and whether current trials should be discontinued.

The considerable body of evidence from randomised controlled trials (RCTs) included in this review indicates either no effect or a relatively small absolute effect size against the complications of influenza. Such an effect, even if statistically significant, would be too small to warrant treatment with NIs in a primary care setting, especially since effective diagnosis and treatments for rare complications (such as pneumonia) are available. Lack of evidence of an effect on hospitalisations probably indicates lack of severity in the first place. Assuming an influenza incidence rate of 2% (similar to that in the control arms of oseltamivir treatment trials), to detect a 25%, clinically significant reduction in pneumonia, 21,500 participants would have to be enrolled in a clinical trial.

Our calculation is likely to underestimate population size, as the 2% incidence rate was derived from trials that used enhanced ad hoc surveillance systems. Any trial design would have to ensure that the presence of complications is ascertained using objective diagnostic criteria (for example, with confirmation using imaging or laboratory testing for pneumonia). Such trials would also have to consider the ethical implications of conducting studies where the estimate of benefit (based on 11 RCTs) in otherwise healthy people is likely to be small, and would have to be balanced against the apparent risks of adverse effects from NIs. We think research should be aimed at more effective preventive measures and early identification of complications.

Based on the length of time it has taken to provide a definitive answer on the efficacy of the NIs, the challenges in obtaining the full information and the methods that we needed to develop to conduct the evidence synthesis, we believe the main implication of our review is the need for reform of multiple components of the research and development, regulatory and assessment pathway of new drugs.

Pharmaceutical sponsors of drug trials should follow a data access and sharing procedure similar to that of the European Medicines Agency (EMA) and sponsors should make all full clinical study reports available to be downloaded from their websites and shared freely once a regulatory decision has been made. Redactions should be kept to the minimum. Part of this process needs to include a full list of the entire drug development programme, to avoid assessment of an incomplete set of trials. Researchers and industry employees who are listed in trial documents should be considered to have legal responsibility for the conduct and reporting of a trial.

Regulators should post an inventory of their documentary holdings on their websites with a brief description of the main content and size of each file. They should make all information available shortly after making a registration decision on a drug and within a reasonable time period. The information should be in electronic format and anonymised (i.e. participants' details should be removed to prevent each person being identified but no further).

Trial registries have improved the reporting of new trials. However, on their own they will not be adequate to resolve the problems we encountered. The completeness of trial registries needs to tested with a random sampling procedure. Clear instructions for the reporting and updating of their content should be promulgated and penalties imposed on breaches of these procedures. Trial registration should include the original and final versions of a trial protocol, with a full declaration of dated amendments. Procedures for trial unblinding and dates of unblinding should be routinely reported. Registration should be made compulsory for all studies in which human beings are randomly assigned to experimental arms. Ethical and consent procedures for all trials should include obligations of the trial sponsor to ensure results are made public. Failure to report the existence of a trial on humans and to make results available should be considered as an ethical breach of conduct and subject to appropriate penalties.

The methods used to conduct our evidence synthesis need to be repeated across further interventions and by other researchers and may need to be refined further. Given the considerable resources involved in using these methods, a system is needed to prioritise reviews of important drugs so that such methods are reserved for drugs that meet certain conditions. Priority could perhaps be given to first drugs of a new family, drugs considered to be innovative or those that are likely to have a big market impact. Such reviews should be publicly funded and be independent from both regulators and manufacturers. Researchers who conduct these 'high scrutiny' reviews need to be free of recent ties to either government or the pharmaceutical industry. Systematic review groups such as The Cochrane Collaboration should consider both adopting these methods for other drugs and whether perhaps to scrutinise the published reviews of prioritised drugs.

Finally, all documentary evidence relating to a trial on humans (including clinical study reports, regulatory documents, evidence syntheses) should be archived electronically with no statute of limitations.

Authors' note: in reviewing over 2 GB of data there is the possibility of mistakes. The authors would be grateful if readers could identify these. We promise that if we concur the record will be amended accordingly.

Acknowledgements

Thanks to Jon Deeks, Timothy Aoki, Carlo Di Pietrantonj, Vittorio Demicheli, Janet Wale, John Bartlett, Sree Nair, Tom Fahey, Matthew Shun-Shin, Anthony Harnden, Nigel Matheson, M Symmonds-Abrahams and Aziz Sheikh, for input and advice on earlier versions of related reviews. Thanks to Ruth Foxlee, Alex Rivetti and Nia Roberts for helping out with the searches. Peter Collignon and Marcus Muellner helped us with aspects of the review. Thanks to Nicola Ring and Ruth Jepson for advice on the inclusion of qualitative data. We thank Toby Lasserson for providing advice and an independent check of our 'Risk of bias' judgements. The European Medicines Agency (EMA) (formerly EMEA) provided all clinical study reports and reviewers' comments in their archive. Hoffman-La Roche SA and GlaxoSmithKline provided us with full clinical study reports and answered our queries. Thanks also to the Australian National Health and Medical Research Council (NHMRC) and the UK National Health Service (NHS) Research and Development fund for grants to enable the 2009 healthy adults review update. Philip Carter and Deborah Cohen shared some of their Freedom of Information material; Eliana Ferroni helped develop and cross-check the TOC. Finally, we wish to thank the following people for commenting on the draft protocol: Maryann Napoli, Janet Wale, Paul Glasziou, David Boltz, Elaine Beller and Anca Zalmanovici Trestioreanu and Marcus Muellner. Thanks to the following people for commenting on the draft 2012 review: Chris Cates, Janet Wale, Paul Glasziou, David Boltz and Robert Ware and the following people for commenting on the draft 2014 review: Chris Cates, Elizabeth Dooley, Janet Wale, David Boltz and Robert Ware.

This project was funded by the NIHR Health Technology Assessment programme and will be published in full in the Health Technology Assessment journal series. Visit the HTA programme website for more details: http://www.nets.nihr.ac.uk/projects/hta/108001. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health. The National Institute of Health Research (NIHR) School of Primary Care Research (SPCR) provides financial support for Dr Carl Heneghan and funding for an investigators' meeting in Oxford (UK).

Data and analyses

Download statistical data

Comparison 1. Oseltamivir versus placebo for treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Time to first alleviation of symptoms in adult treatment (ITT population)83954Mean Difference (IV, Random, 95% CI)-16.76 [-25.10, -8.42]
2 Hospital admission in adult treatment (safety population)74394Risk Ratio (IV, Random, 95% CI)0.92 [0.57, 1.50]
3 Defined as influenza-infected at baseline in adult treatment84452Risk Ratio (IV, Random, 95% CI)0.95 [0.91, 0.99]
4 Antibody rise four-fold or greater in adult treatment84025Risk Ratio (IV, Random, 95% CI)0.92 [0.86, 0.97]
5 Adverse events - nausea in adult treatment (on-treatment)84452Risk Ratio (IV, Random, 95% CI)1.57 [1.14, 2.15]
6 Adverse events - vomiting in adult treatment (on-treatment)84452Risk Ratio (IV, Random, 95% CI)2.43 [1.75, 3.38]
7 Adverse events - diarrhoea in adult treatment (on-treatment)84452Risk Ratio (IV, Random, 95% CI)0.67 [0.46, 0.98]
8 Withdrawal from adult treatment trial due to adverse events84452Risk Ratio (IV, Random, 95% CI)0.91 [0.56, 1.48]
9 All withdrawals from adult treatment84452Risk Ratio (IV, Random, 95% CI)1.02 [0.73, 1.41]
10 Adverse events - cough in adult treatment (on-treatment)63943Risk Ratio (IV, Random, 95% CI)0.63 [0.41, 0.96]
11 Adverse events - abdominal pain in adult treatment (on-treatment)64368Risk Ratio (IV, Random, 95% CI)1.00 [0.64, 1.55]
12 Adverse events: dizziness in adult treatment (on-treatment)84452Risk Ratio (IV, Random, 95% CI)0.77 [0.51, 1.18]
13 Adverse events: headache in adult treatment (on-treatment)74426Risk Ratio (IV, Random, 95% CI)1.17 [0.72, 1.90]
14 Serious adverse events: overall in adult treatment (on-treatment)74394Risk Ratio (IV, Random, 95% CI)0.96 [0.51, 1.80]
15 Serious adverse events: overall in adult treatment (off-treatment)74394Risk Ratio (IV, Random, 95% CI)0.73 [0.39, 1.37]
16 Complications: bronchitis in adult treatment84452Risk Ratio (IV, Random, 95% CI)0.75 [0.56, 1.01]
16.1 Trials which collected data on non-specific adverse event or secondary/intercurrent illness form63316Risk Ratio (IV, Random, 95% CI)0.66 [0.42, 1.03]
16.2 Trials which collected data on specific "Diagnosis of secondary illness" form21136Risk Ratio (IV, Random, 95% CI)0.87 [0.61, 1.26]
17 Complications: pneumonia in adult treatment84452Risk Ratio (IV, Random, 95% CI)0.55 [0.33, 0.90]
17.1 Trials which collected data on non-specific adverse event or secondary/intercurrent illness form63316Risk Ratio (IV, Random, 95% CI)0.44 [0.22, 0.88]
17.2 Trials which collected data on specific "Diagnosis of secondary illness" form21136Risk Ratio (IV, Random, 95% CI)0.69 [0.33, 1.44]
18 Complications: sinusitis in adult treatment84452Risk Ratio (IV, Random, 95% CI)1.03 [0.76, 1.40]
18.1 Trials which collected data on non-specific adverse event or secondary/intercurrent illness form63316Risk Ratio (IV, Random, 95% CI)1.05 [0.74, 1.50]
18.2 Trials which collected data on specific "Diagnosis of secondary illness" form21136Risk Ratio (IV, Random, 95% CI)0.97 [0.52, 1.80]
19 Complications: otitis media in adult treatment64368Risk Ratio (IV, Random, 95% CI)1.11 [0.57, 2.15]
19.1 Trials which collected data on non-specific adverse event or secondary/intercurrent illness form43232Risk Ratio (IV, Random, 95% CI)0.99 [0.46, 2.12]
19.2 Trials which collected data on specific "Diagnosis of secondary illness" form21136Risk Ratio (IV, Random, 95% CI)1.57 [0.41, 6.02]
20 Complications in adult trials classified as serious or leading to study withdrawal63675Risk Ratio (IV, Random, 95% CI)0.91 [0.40, 2.06]
21 Culture-positive at baseline in adult treatment84452Risk Ratio (IV, Random, 95% CI)1.01 [0.95, 1.07]
22 Adverse events: general body system in adult treatment (on-treatment)84452Risk Ratio (IV, Random, 95% CI)0.88 [0.67, 1.17]
23 Adverse events: neurological body system in adult treatment (on-treatment)84452Risk Ratio (IV, Random, 95% CI)1.05 [0.80, 1.38]
24 Adverse events: respiratory body system in adult treatment (on-treatment)84452Risk Ratio (IV, Random, 95% CI)0.81 [0.65, 1.00]
25 Adverse events: infection body system in adult treatment (on-treatment)84452Risk Ratio (IV, Random, 95% CI)0.85 [0.71, 1.01]
26 Adverse events: gastrointestinal body system in adult treatment (on-treatment)84452Risk Ratio (IV, Random, 95% CI)1.25 [1.08, 1.45]
27 Adverse events: cardiac body system in adult treatment (on-treatment)63943Risk Ratio (IV, Random, 95% CI)0.49 [0.25, 0.97]
28 Adverse events: ear body system in adult treatment (on-treatment)74426Risk Ratio (IV, Random, 95% CI)0.99 [0.61, 1.60]
29 Adverse events: eye body system in adult treatment (on-treatment)74426Risk Ratio (IV, Random, 95% CI)1.00 [0.52, 1.92]
30 Adverse events: metabolism body system in adult treatment (on-treatment)74394Risk Ratio (IV, Random, 95% CI)0.81 [0.46, 1.43]
31 Adverse events: musculoskeletal body system in adult treatment (on-treatment)84452Risk Ratio (IV, Random, 95% CI)1.01 [0.59, 1.73]
32 Adverse events: psychiatric body system in adult treatment (on-treatment)74426Risk Ratio (IV, Random, 95% CI)0.93 [0.43, 2.03]
33 Adverse events: skin body system in adult treatment (on-treatment)74426Risk Ratio (IV, Random, 95% CI)1.14 [0.63, 2.06]
34 Adverse events: cardiac body system in adult treatment (off-treatment)74394Risk Ratio (IV, Random, 95% CI)1.21 [0.55, 2.64]
35 Adverse events: ear body system in adult treatment (off-treatment)64368Risk Ratio (IV, Random, 95% CI)1.17 [0.57, 2.42]
36 Adverse events: gastrointestinal body system in adult treatment (off-treatment)74394Risk Ratio (IV, Random, 95% CI)1.08 [0.74, 1.58]
37 Adverse events: general body system in adult treatment (off-treatment)74394Risk Ratio (IV, Random, 95% CI)0.90 [0.50, 1.62]
38 Adverse events: infection body system in adult treatment (off-treatment)74426Risk Ratio (IV, Random, 95% CI)0.80 [0.61, 1.03]
39 Adverse events: musculoskeletal body system in adult treatment (off-treatment)74394Risk Ratio (IV, Random, 95% CI)0.84 [0.54, 1.30]
40 Adverse events: neurological body system in adult treatment (off-treatment)64368Risk Ratio (IV, Random, 95% CI)1.29 [0.87, 1.91]
41 Adverse events: respiratory body system in adult treatment (off-treatment)84452Risk Ratio (IV, Random, 95% CI)0.94 [0.71, 1.24]
42 Adverse events: skin body system in adult treatment (off-treatment)84452Risk Ratio (IV, Random, 95% CI)0.81 [0.42, 1.56]
43 Adverse events: cough in adult treatment (off-treatment)84452Risk Ratio (IV, Random, 95% CI)1.01 [0.55, 1.85]
44 Adverse events: headache in adult treatment (off-treatment)64368Risk Ratio (IV, Random, 95% CI)1.34 [0.83, 2.15]
45 Adverse events: nausea in adult treatment (off-treatment)64368Risk Ratio (IV, Random, 95% CI)1.05 [0.50, 2.23]
46 Time to first alleviation of symptoms in child treatment [hours]31329Mean Difference (IV, Random, 95% CI)-8.04 [-33.34, 17.26]
46.1 Otherwise healthy children1669Mean Difference (IV, Random, 95% CI)-29.40 [-47.04, -11.76]
46.2 Children with chronic asthma2660Mean Difference (IV, Random, 95% CI)5.18 [-11.06, 21.41]
47 Hospital admission in child treatment (safety population)31359Risk Ratio (IV, Random, 95% CI)1.92 [0.70, 5.23]
48 Defined as influenza-infected at baseline in child treatment31359Risk Ratio (IV, Random, 95% CI)0.92 [0.84, 1.01]
49 Antibody rise four-fold or greater in child treatment2909Risk Ratio (M-H, Random, 95% CI)0.90 [0.80, 1.00]
50 Complications: bronchitis in child treatment31359Risk Ratio (IV, Random, 95% CI)0.65 [0.27, 1.55]
51 Complications: otitis media in child treatment31359Risk Ratio (IV, Random, 95% CI)0.80 [0.62, 1.02]
52 Complications: pneumonia in child treatment31359Risk Ratio (IV, Random, 95% CI)1.06 [0.62, 1.83]
53 Complications: sinusitis in child treatment31359Risk Ratio (IV, Random, 95% CI)1.00 [0.58, 1.72]
54 Complications: pneumonia in child treatment by on- and off-treatment3 Risk Ratio (IV, Random, 95% CI)Subtotals only
54.1 On-treatment31359Risk Ratio (IV, Random, 95% CI)0.87 [0.48, 1.60]
54.2 Off-treatment31359Risk Ratio (IV, Random, 95% CI)2.83 [0.52, 15.31]
55 Complications in trials of children classified as serious or leading to study withdrawal31359Risk Ratio (IV, Random, 95% CI)1.98 [0.58, 6.72]
56 Withdrawal from child treatment trial due to adverse events21029Risk Ratio (IV, Random, 95% CI)0.99 [0.33, 3.01]
57 All withdrawals from child treatment21029Risk Ratio (IV, Random, 95% CI)0.94 [0.56, 1.60]
58 Serious adverse events: overall in child treatment (on-treatment)21029Risk Ratio (IV, Random, 95% CI)1.97 [0.59, 6.56]
59 Serious adverse events: overall in child treatment (off-treatment)31358Risk Ratio (M-H, Fixed, 95% CI)1.80 [0.38, 8.46]
60 Adverse events: abdominal pain in child treatment (on-treatment)31358Risk Ratio (IV, Random, 95% CI)1.10 [0.62, 1.95]
61 Adverse events: diarrhoea in child treatment (on-treatment)31358Risk Ratio (IV, Random, 95% CI)0.87 [0.58, 1.28]
62 Adverse events: nausea in child treatment (on-treatment)31358Risk Ratio (IV, Random, 95% CI)0.87 [0.50, 1.51]
63 Adverse events: vomiting in child treatment (on-treatment)31358Risk Ratio (IV, Random, 95% CI)1.70 [1.23, 2.35]
64 Adverse events: abdominal pain in child treatment (off-treatment)31358Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.39, 2.11]
65 Adverse events: cough in child treatment (off-treatment)21029Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.27, 1.85]
66 Adverse events: diarrhoea in child treatment (off-treatment)31358Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.36, 1.40]
67 Adverse events: headache in child treatment (off-treatment)31358Risk Ratio (IV, Random, 95% CI)1.13 [0.55, 2.34]
68 Adverse events: vomiting in child treatment (off-treatment)31358Risk Ratio (M-H, Random, 95% CI)1.07 [0.57, 2.02]
69 Adverse events: ear body system in child treatment (on-treatment)31358Risk Ratio (IV, Random, 95% CI)1.18 [0.30, 4.56]
70 Adverse events: gastrointestinal body system in child treatment (on-treatment)31358Risk Ratio (IV, Random, 95% CI)1.18 [0.96, 1.44]
71 Adverse events: general body system in child treatment (on-treatment)31358Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.47, 1.92]
72 Adverse events: infection body system in child treatment (on-treatment)31358Risk Ratio (IV, Random, 95% CI)0.75 [0.59, 0.95]
73 Adverse events: neurological body system in child treatment (on-treatment)31358Risk Ratio (IV, Random, 95% CI)0.66 [0.17, 2.62]
74 Adverse events: respiratory body system in child treatment (on-treatment)31358Risk Ratio (IV, Random, 95% CI)1.02 [0.73, 1.43]
75 Adverse events: skin body system in child treatment (on-treatment)31358Risk Ratio (IV, Random, 95% CI)1.26 [0.71, 2.22]
76 Adverse events: ear body system in child treatment (off-treatment)31358Risk Ratio (IV, Random, 95% CI)1.10 [0.52, 2.32]
77 Adverse events: gastrointestinal body system in child treatment (off-treatment)21029Risk Ratio (IV, Random, 95% CI)1.15 [0.69, 1.91]
78 Adverse events: general body system in child treatment (off-treatment)31358Risk Ratio (IV, Random, 95% CI)1.00 [0.54, 1.86]
79 Adverse events: infection body system in child treatment (off-treatment)31358Risk Ratio (IV, Random, 95% CI)1.14 [0.82, 1.58]
80 Adverse events: neurological body system in child treatment (off-treatment)31358Risk Ratio (IV, Random, 95% CI)1.07 [0.51, 2.26]
81 Adverse events: respiratory body system in child treatment (off-treatment)31358Risk Ratio (IV, Random, 95% CI)0.94 [0.65, 1.35]
82 Culture-positive at baseline in child treatment31359Risk Ratio (IV, Random, 95% CI)0.93 [0.83, 1.04]
Analysis 1.1.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 1 Time to first alleviation of symptoms in adult treatment (ITT population).

Analysis 1.2.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 2 Hospital admission in adult treatment (safety population).

Analysis 1.3.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 3 Defined as influenza-infected at baseline in adult treatment.

Analysis 1.4.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 4 Antibody rise four-fold or greater in adult treatment.

Analysis 1.5.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 5 Adverse events - nausea in adult treatment (on-treatment).

Analysis 1.6.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 6 Adverse events - vomiting in adult treatment (on-treatment).

Analysis 1.7.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 7 Adverse events - diarrhoea in adult treatment (on-treatment).

Analysis 1.8.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 8 Withdrawal from adult treatment trial due to adverse events.

Analysis 1.9.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 9 All withdrawals from adult treatment.

Analysis 1.10.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 10 Adverse events - cough in adult treatment (on-treatment).

Analysis 1.11.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 11 Adverse events - abdominal pain in adult treatment (on-treatment).

Analysis 1.12.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 12 Adverse events: dizziness in adult treatment (on-treatment).

Analysis 1.13.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 13 Adverse events: headache in adult treatment (on-treatment).

Analysis 1.14.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 14 Serious adverse events: overall in adult treatment (on-treatment).

Analysis 1.15.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 15 Serious adverse events: overall in adult treatment (off-treatment).

Analysis 1.16.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 16 Complications: bronchitis in adult treatment.

Analysis 1.17.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 17 Complications: pneumonia in adult treatment.

Analysis 1.18.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 18 Complications: sinusitis in adult treatment.

Analysis 1.19.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 19 Complications: otitis media in adult treatment.

Analysis 1.20.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 20 Complications in adult trials classified as serious or leading to study withdrawal.

Analysis 1.21.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 21 Culture-positive at baseline in adult treatment.

Analysis 1.22.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 22 Adverse events: general body system in adult treatment (on-treatment).

Analysis 1.23.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 23 Adverse events: neurological body system in adult treatment (on-treatment).

Analysis 1.24.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 24 Adverse events: respiratory body system in adult treatment (on-treatment).

Analysis 1.25.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 25 Adverse events: infection body system in adult treatment (on-treatment).

Analysis 1.26.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 26 Adverse events: gastrointestinal body system in adult treatment (on-treatment).

Analysis 1.27.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 27 Adverse events: cardiac body system in adult treatment (on-treatment).

Analysis 1.28.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 28 Adverse events: ear body system in adult treatment (on-treatment).

Analysis 1.29.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 29 Adverse events: eye body system in adult treatment (on-treatment).

Analysis 1.30.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 30 Adverse events: metabolism body system in adult treatment (on-treatment).

Analysis 1.31.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 31 Adverse events: musculoskeletal body system in adult treatment (on-treatment).

Analysis 1.32.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 32 Adverse events: psychiatric body system in adult treatment (on-treatment).

Analysis 1.33.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 33 Adverse events: skin body system in adult treatment (on-treatment).

Analysis 1.34.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 34 Adverse events: cardiac body system in adult treatment (off-treatment).

Analysis 1.35.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 35 Adverse events: ear body system in adult treatment (off-treatment).

Analysis 1.36.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 36 Adverse events: gastrointestinal body system in adult treatment (off-treatment).

Analysis 1.37.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 37 Adverse events: general body system in adult treatment (off-treatment).

Analysis 1.38.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 38 Adverse events: infection body system in adult treatment (off-treatment).

Analysis 1.39.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 39 Adverse events: musculoskeletal body system in adult treatment (off-treatment).

Analysis 1.40.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 40 Adverse events: neurological body system in adult treatment (off-treatment).

Analysis 1.41.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 41 Adverse events: respiratory body system in adult treatment (off-treatment).

Analysis 1.42.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 42 Adverse events: skin body system in adult treatment (off-treatment).

Analysis 1.43.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 43 Adverse events: cough in adult treatment (off-treatment).

Analysis 1.44.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 44 Adverse events: headache in adult treatment (off-treatment).

Analysis 1.45.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 45 Adverse events: nausea in adult treatment (off-treatment).

Analysis 1.46.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 46 Time to first alleviation of symptoms in child treatment [hours].

Analysis 1.47.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 47 Hospital admission in child treatment (safety population).

Analysis 1.48.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 48 Defined as influenza-infected at baseline in child treatment.

Analysis 1.49.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 49 Antibody rise four-fold or greater in child treatment.

Analysis 1.50.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 50 Complications: bronchitis in child treatment.

Analysis 1.51.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 51 Complications: otitis media in child treatment.

Analysis 1.52.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 52 Complications: pneumonia in child treatment.

Analysis 1.53.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 53 Complications: sinusitis in child treatment.

Analysis 1.54.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 54 Complications: pneumonia in child treatment by on- and off-treatment.

Analysis 1.55.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 55 Complications in trials of children classified as serious or leading to study withdrawal.

Analysis 1.56.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 56 Withdrawal from child treatment trial due to adverse events.

Analysis 1.57.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 57 All withdrawals from child treatment.

Analysis 1.58.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 58 Serious adverse events: overall in child treatment (on-treatment).

Analysis 1.59.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 59 Serious adverse events: overall in child treatment (off-treatment).

Analysis 1.60.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 60 Adverse events: abdominal pain in child treatment (on-treatment).

Analysis 1.61.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 61 Adverse events: diarrhoea in child treatment (on-treatment).

Analysis 1.62.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 62 Adverse events: nausea in child treatment (on-treatment).

Analysis 1.63.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 63 Adverse events: vomiting in child treatment (on-treatment).

Analysis 1.64.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 64 Adverse events: abdominal pain in child treatment (off-treatment).

Analysis 1.65.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 65 Adverse events: cough in child treatment (off-treatment).

Analysis 1.66.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 66 Adverse events: diarrhoea in child treatment (off-treatment).

Analysis 1.67.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 67 Adverse events: headache in child treatment (off-treatment).

Analysis 1.68.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 68 Adverse events: vomiting in child treatment (off-treatment).

Analysis 1.69.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 69 Adverse events: ear body system in child treatment (on-treatment).

Analysis 1.70.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 70 Adverse events: gastrointestinal body system in child treatment (on-treatment).

Analysis 1.71.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 71 Adverse events: general body system in child treatment (on-treatment).

Analysis 1.72.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 72 Adverse events: infection body system in child treatment (on-treatment).

Analysis 1.73.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 73 Adverse events: neurological body system in child treatment (on-treatment).

Analysis 1.74.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 74 Adverse events: respiratory body system in child treatment (on-treatment).

Analysis 1.75.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 75 Adverse events: skin body system in child treatment (on-treatment).

Analysis 1.76.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 76 Adverse events: ear body system in child treatment (off-treatment).

Analysis 1.77.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 77 Adverse events: gastrointestinal body system in child treatment (off-treatment).

Analysis 1.78.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 78 Adverse events: general body system in child treatment (off-treatment).

Analysis 1.79.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 79 Adverse events: infection body system in child treatment (off-treatment).

Analysis 1.80.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 80 Adverse events: neurological body system in child treatment (off-treatment).

Analysis 1.81.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 81 Adverse events: respiratory body system in child treatment (off-treatment).

Analysis 1.82.

Comparison 1 Oseltamivir versus placebo for treatment, Outcome 82 Culture-positive at baseline in child treatment.

Comparison 2. Oseltamivir versus placebo for prophylaxis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Symptomatic influenza in adult prophylaxis of individuals32479Risk Ratio (IV, Random, 95% CI)0.45 [0.30, 0.67]
2 Asymptomatic influenza in adult prophylaxis of individuals32479Risk Ratio (IV, Random, 95% CI)0.78 [0.49, 1.24]
3 Symptomatic influenza in household prophylaxis1405Risk Ratio (IV, Random, 95% CI)0.20 [0.09, 0.44]
4 Asymptomatic influenza in household prophylaxis1405Risk Ratio (IV, Random, 95% CI)1.14 [0.39, 3.33]
5 Influenza-like illness reported as adverse event (on-treatment)43434Risk Ratio (IV, Random, 95% CI)0.99 [0.73, 1.35]
6 Influenza-like illness reported as adverse event (off-treatment)43434Risk Ratio (IV, Random, 95% CI)0.62 [0.34, 1.16]
7 Hospitalisation in adult prophylaxis (safety population)43434Risk Ratio (IV, Random, 95% CI)1.14 [0.66, 1.94]
8 Complications: bronchitis in adult prophylaxis43434Risk Ratio (IV, Random, 95% CI)0.74 [0.41, 1.35]
9 Complications: sinusitis in adult prophylaxis43434Risk Ratio (IV, Random, 95% CI)1.41 [0.75, 2.62]
10 Adverse events leading to study withdrawal in adult prophylaxis43434Risk Ratio (IV, Random, 95% CI)1.11 [0.57, 2.18]
11 All withdrawals in adult prophylaxis43434Risk Ratio (IV, Random, 95% CI)1.15 [0.82, 1.61]
12 Serious adverse events in adult prophylaxis (on-treatment)32479Risk Ratio (IV, Random, 95% CI)0.94 [0.53, 1.66]
13 Serious adverse events in adult prophylaxis (off-treatment)43434Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.57, 2.60]
14 Adverse events: abdominal pain in adult prophylaxis (on-treatment)43434Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.77, 1.82]
15 Adverse events: cough in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)0.96 [0.68, 1.36]
16 Adverse events: diarrhoea in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)1.09 [0.64, 1.86]
17 Adverse events: dizziness in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)1.15 [0.66, 2.01]
18 Adverse events: fatigue in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)1.12 [0.89, 1.40]
19 Adverse events: headache in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)1.18 [1.05, 1.33]
20 Adverse events: nausea in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)1.96 [1.20, 3.20]
21 Adverse events: vomiting in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)1.91 [0.70, 5.22]
22 Adverse events: cough in adult prophylaxis (off-treatment)32479Risk Ratio (IV, Random, 95% CI)0.72 [0.36, 1.45]
23 Adverse events: fatigue in adult prophylaxis (off-treatment)32479Risk Ratio (IV, Random, 95% CI)1.33 [0.57, 3.13]
24 Adverse events: headache in adult prophylaxis (off-treatment)43434Risk Ratio (IV, Random, 95% CI)0.88 [0.63, 1.24]
25 Adverse events: blood body system in adult prophylaxis (on-treatment)32479Risk Ratio (IV, Random, 95% CI)0.99 [0.30, 3.25]
26 Adverse events: cardiac body system in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)0.75 [0.36, 1.58]
27 Adverse events: ear body system in adult prophylaxis (on treatment)43434Risk Ratio (IV, Random, 95% CI)1.44 [0.61, 3.40]
28 Adverse events: eye body system in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)1.01 [0.56, 1.81]
29 Adverse events: gastrointestinal body system in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)1.38 [1.17, 1.63]
30 Adverse events: general body system in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)1.03 [0.88, 1.20]
31 Adverse events: infection body system in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)0.97 [0.84, 1.11]
32 Adverse events: immune body system in adult prophylaxis (on-treatment)11559Risk Ratio (IV, Random, 95% CI)0.86 [0.45, 1.64]
33 Adverse events: injury body system in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)0.97 [0.60, 1.56]
34 Adverse events: metabolism body system in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)1.36 [0.73, 2.54]
35 Adverse events: musculoskeletal body system in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)0.98 [0.79, 1.22]
36 Adverse events: neurological body system in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)1.21 [1.03, 1.42]
37 Adverse events: psychiatric body system in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)1.81 [0.97, 3.37]
38 Adverse events: renal body system in adult prophylaxis (on-treatment)32479Risk Ratio (IV, Random, 95% CI)3.17 [0.96, 10.49]
39 Adverse events: reproductive body system in adult prophylaxis (on treatment)43434Risk Ratio (IV, Random, 95% CI)1.05 [0.77, 1.42]
40 Adverse events: respiratory body system in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)1.04 [0.90, 1.20]
41 Adverse events: skin body system in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)0.92 [0.63, 1.34]
42 Adverse events: surgical events in adult prophylaxis (on-treatment)43434Risk Ratio (IV, Random, 95% CI)0.98 [0.42, 2.29]
43 Adverse events: vascular body system in adult prophylaxis (on-treatment)32479Risk Ratio (IV, Random, 95% CI)0.90 [0.45, 1.80]
44 Adverse events: cardiac body system in adult prophylaxis (off-treatment)43434Risk Ratio (IV, Random, 95% CI)1.50 [0.67, 3.35]
45 Adverse events: gastrointestinal body system in adult prophylaxis (off-treatment)43434Risk Ratio (IV, Random, 95% CI)0.98 [0.62, 1.53]
46 Adverse events: general body system in adult prophylaxis (off-treatment)43434Risk Ratio (IV, Random, 95% CI)1.02 [0.69, 1.49]
47 Adverse events: infection body system in adult prophylaxis (off-treatment)43434Risk Ratio (IV, Random, 95% CI)0.89 [0.68, 1.17]
48 Adverse events: injury body system in adult prophylaxis (off-treatment)43434Risk Ratio (IV, Random, 95% CI)1.01 [0.49, 2.09]
49 Adverse events: musculoskeletal body system in adult prophylaxis (off-treatment)43434Risk Ratio (IV, Random, 95% CI)1.04 [0.63, 1.72]
50 Adverse events: neurological body system in adult prophylaxis (off-treatment)43434Risk Ratio (IV, Random, 95% CI)0.93 [0.68, 1.28]
51 Adverse events: reproductive body system in adult prophylaxis (off-treatment)22514Risk Ratio (IV, Random, 95% CI)0.49 [0.24, 1.00]
52 Adverse events: respiratory body system in adult prophylaxis (off-treatment)43434Risk Ratio (IV, Random, 95% CI)0.95 [0.69, 1.32]
53 Adverse events: skin body system in adult prophylaxis (off-treatment)43434Risk Ratio (IV, Random, 95% CI)0.73 [0.32, 1.69]
54 Adverse events: psychiatric body system in adult prophylaxis (on and off-treatment)43434Risk Ratio (IV, Random, 95% CI)1.80 [1.05, 3.08]
55 Adverse events: renal body system in adult prophylaxis (on and off-treatment)43434Risk Ratio (IV, Random, 95% CI)2.01 [0.74, 5.47]
Analysis 2.1.

Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 1 Symptomatic influenza in adult prophylaxis of individuals.

Analysis 2.2.

Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 2 Asymptomatic influenza in adult prophylaxis of individuals.

Analysis 2.3.

Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 3 Symptomatic influenza in household prophylaxis.

Analysis 2.4.

Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 4 Asymptomatic influenza in household prophylaxis.

Analysis 2.5.

Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 5 Influenza-like illness reported as adverse event (on-treatment).

Analysis 2.6.

Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 6 Influenza-like illness reported as adverse event (off-treatment).

Analysis 2.7.

Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 7 Hospitalisation in adult prophylaxis (safety population).

Analysis 2.8.

Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 8 Complications: bronchitis in adult prophylaxis.

Analysis 2.9.

Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 9 Complications: sinusitis in adult prophylaxis.

Analysis 2.10.

Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 10 Adverse events leading to study withdrawal in adult prophylaxis.

Analysis 2.11.

Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 11 All withdrawals in adult prophylaxis.

Analysis 2.12.

Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 12 Serious adverse events in adult prophylaxi