JAMA viewpoint on using observational studies

Announcement Date: October 19, 2015

The authors judge the randomized controlled trial (RCT) evidence as inadequate as RCTs have not been carried out in “high risk
populations” which they defined as including children and elderly.


Louie JK, Lampiris H. Treating Influenza With Neuraminidase Inhibitors: What Is the Evidence? JAMA Intern Med. 2015 Oct 19;1.

“In conclusion, the available evidence suggests that the effect of neuraminidase inhibitors on morbidity and mortality from influenza depends on the population being treated and the setting. The findings from the Cochrane reviews are important,but the trials were performed with a specific population (healthy outpatients) and a different outcome (duration of symptoms rather than assessment of pneumonia or mortality) in mind”.

Doshi P, Jefferson T. Treating Influenza With Neuraminidase Inhibitors: What Is the Evidence?

Concerns about this article Posted on October 28, 2015

Dear editor, we are writing with concerns about what we think are inaccurate and misleading statements in the Viewpoint on influenza antivirals by Louie and Lampiris (Louie 2015). We summarize our concerns below.

Louie and Lampiris define “high risk” populations as including young children and the elderly, and state that randomized controlled trials (RCTs) have not been carried out in high-risk populations. This is false. Multiple RCTs analyzed in our Cochrane review (Jefferson 2014) were in such populations (e.g. trials WV15708, WV15825, WV15758, and WV15759/WV15871). In addition, elderly patients participated in trials such as M76001. Based on RCTs alone, Roche wrote in 2003 that oseltamivir treatment reduces complications and hospitalizations in “at-risk” adults (Kaiser 2003).

Louie and Lampiris describe a Roche funded study published in 2015. They note: “Of the four authors, one reported receiving fees from Roche and another company outside the submitted work, and another reported receiving travel funding from Roche.” This is incomplete. In fact, not two but all four authors have financial conflicts of interest. One author (RJW) does not inform readers that Gilead Sciences is the patent holder for oseltamivir; another (JD) declares \”no competing interests” but her salary was supported by Roche while she carried out the analysis; a third (SP) declares “no competing interests” but Stuart Pocock told The BMJ (Lenzer 2015) that he received research funds from Gilead and Genentech. These facts have been documented for months in the following places: (Read More)

Doshi P, Jefferson T. Neuraminidase Inhibitors and Influenza Infection. JAMA Intern Med. 2016;176(3):415-416. doi:10.1001/jamainternmed.2016.0016.

To the Editor As authors of articles cited by Louis and Lampiris,1 we have a different view of the evidence that should inform recommendations about treating influenza with neuraminidase inhibitors.

Louis and Lampiris champion conclusions from observational studies. They judged the evidence from randomized clinical trials as inadequate because such trials have not been carried out in high-risk populations, which they defined as including children and the elderly. However, we analyzed 13 such placebo-controlled randomized clinical trials in our Cochrane review.2

Based on randomized clinical trials, the manufacturer of oseltamivir (Tamiflu; Roche Pharmaceuticals) has claimed that treatment reduces complications and hospitalizations in at-risk adults.3 Our review, however, found this claim unsubstantiated in the elderly population and in children.2 In children with asthma, oseltamivir did not shorten the duration of symptoms. Our review found that oseltamivir may impede the production of influenza antibodies and cause renal and psychiatric harms. Because of flaws in trial design, there is no convincing evidence it can interrupt person-to-person spread of influenza virus.

Louie JK, Lampiris H. Neuraminidase Inhibitors and Influenza Infection—Reply. JAMA Intern Med. 2016;176(3):416-417. doi:10.1001/jamainternmed.2016.0050.

In their Cochrane review, Jefferson and Doshi have conducted a thorough and rigorous analysis of the available randomized clinical trial (RCT) data. However, the authors themselves acknowledge the limitations of their conclusions given the quality of the studies reviewed, stating: “Hospitalizations 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.”Cochrane reviews set rigorous standards for deciding which studies to include, preferentially including RCTs over observational studies, and typically result in conservative recommendations. However, the inability to show benefit under the most rigorous study conditions does not mean that benefit does not exist.3 Given this, it is reasonable to consider the available non-RCT data when evaluating the usefulness of neuraminidase inhibitor drugs (NAI) for influenza.