The Centers for Disease Control and Prevention (CDC) has boiled down its public health campaign against influenza to a single slogan: "Take 3." Vaccines, everyday preventive actions like handwashing, and influenza antivirals.
Last year, because of a mismatch between the vaccine and circulating virus, the message was reduced to—essentially—"Take 1," as the CDC emphatically promoted oseltamivir (Tamiflu) for treating disease. The agency has stated: "Antiviral flu medicines are underutilized. If you get them early, they could keep you out of the hospital and might even save your life."
The CDC is one of the nation's most powerful voices when it comes to public health recommendations. That's why it's so important that its advice be scientifically sound and independently derived. Unfortunately, the CDC's advice on Tamiflu is neither. Here we explain why — and offer suggestions for what to do about it.
Tamiflu For All
CDC recommendations focus on treating those at higher risk of complications of influenza, and generally speak of "influenza antivirals" without reference to a specific product. However, oseltamivir is the only neuraminidase inhibitor in pill form. Further, the CDC holds that treatment "can be considered for any previously healthy, symptomatic outpatient," and also can be initiated beyond the FDA-approved two-day timeframe, creating a de-facto "Tamiflu for all" national recommendation.
While CDC states that oseltamivir can prevent serious complications and even death, by contrast, potential harms are not consistently highlighted alongside promotions of the drug and were not mentioned at the CDC's press conference. This oversight is conspicuous given high rates of nausea and vomiting associated with oseltamivir and recent analyses that raised concerns over possible renal harms and neuropsychiatric adverse events.
A Closer Look At The Evidence
Many of the CDC's statements are either contradicted by other prominent groups or are only supported by observational studies (Table 1).
Table 1. Sample Evidentiary Claims Underpinning Current CDC Recommendations For Treatment With Oseltamivir
| Evidentiary claims | Type of evidence CDC cites in support of claim | What others say |
| Reduced risk of complications of influenza: pneumonia | Pooled analysis of 10 RCTs, funded by manufacturer | FDA: "The data we've reviewed do not support this claim."
FDA approved label: "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." |
| Reduced risk of complications of influenza: otitis media in children | 2 RCTs, funded by manufacturer | Cochrane: "Neither neuraminidase inhibitor significantly reduced the risk of otitis media and sinusitis in both adults and children." |
| Reduced risk of hospitalizations | Pooled analysis of 10 RCTs, funded by manufacturer | FDA: "[Oseltamivir] has not been proven to have a positive impact on the potential consequences (such as hospitalizations, mortality, or economic impact) of seasonal, avian, or pandemic influenza." |
| Reduced risk of mortality | 1 observational study, without manufacturer funding
"Many observational studies" (uncited) | FDA: "The data we've reviewed do not support this claim." |
| Reduced duration of symptoms in adults | 3 RCTs, funded by manufacturer | FDA approved label: "1.3 day reduction in the median time to improvement in influenza-infected subjects receiving Tamiflu compared to subjects receiving placebo." |
For example, the CDC's official recommendations for influenza antivirals—a lengthy document last updated in 2011—claims statistically significant reductions in pneumonia and hospitalizations among adults treated with oseltamivir, citing a manufacturer authored pooled analysis of 10 randomized trials. The Food and Drug Administration (FDA) however—which had complete access to all trial data comprising the research program for oseltamivir—formally instructed Roche to cease from making a claim about reducing influenza complications in promotional materials.
In addition, it required Roche to print on the product label: "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." Similarly, Cochrane reviewers determined that there was no compelling evidence to conclude the drug reduces the risk of serious complications such as pneumonia or hospitalizations.
The CDC's contention that influenza antivirals save lives is even more problematic. While the agency has promoted this as a key take-home message, the claim is based entirely on uncontrolled, retrospective observational studies, most from a single influenza season (2009-2010). CDC's reliance on observational studies makes apparent the fact that we lack more robust randomized trials demonstrating an alleged effect against mortality. But the agency's position is hard to reconcile with its own more technical evaluation: a World Health Organization (WHO)-sponsored and CDC co-authored systematic review of the observational studies cast serious doubts on their reliability, formally rating the quality of the data as "low." An additional concern is that the CDC's claim is, once again, directly contradicted by the FDA, which has stated that the data they reviewed did not support reduction in mortality by influenza antivirals.
CDC's advice is not derived from independent analysis of oseltamivir clinical trial data. Instead of scrutinizing the raw trial data the way FDA routinely does, CDC relies on journal publications. This practice seems particularly ill-advised in the case of influenza antivirals since the majority of treatment trials of oseltamivir have never been published in journals and evidence that systematic reviews of neuraminidase inhibitors funded by industry have more optimistic conclusions than those authored by independent parties. In April 2014, Cochrane released a comprehensive set of formerly confidential clinical study reports on oseltamivir and zanamivir, but to date the CDC has not indicated an intention to review these and update their recommendations.
Other countries have been more self-critical and are re-evaluating the evidence supporting national policies for influenza antivirals. The UK Parliamentary Accounts Committee, for example, led an investigation into the £424 million spent by the government on oseltamivir, ultimately concluding that the case for stockpiling was "based on judgement rather than on evidence." In Germany, prominent civil society organizations are likewise questioning the substantial government investments in influenza antivirals and calling for a re-examination of the role of these drugs in public health programs.
What We Need
The open data movement is creating new cultural norms for assessing the benefits of therapies and the public deserves an open process in the use of these data for developing public health guidelines. In order to ensure that guidelines reflect comprehensive, objective appraisals of all available data, we propose the following key principles:
Transparency
The process of developing broad public health recommendations demands high-quality evidence and rigorous and transparent methods. These methods should be pre-specified, documented in detail, and publicly available. In the presence of inadequate or contradictory information, the CDC's guidelines should be conservative in their endorsement of any intervention and present safety issues alongside known benefits. The similarities and differences in working assumptions regarding safety or efficacy as compared to the FDA should be discussed and recommendations should be regularly updated as new evidence emerges with data sources underpinning guidance clearly delineated.
Underlying Trial Data
The increasing public availability of trial data that previously was only shared with regulators creates an obligation to review these data. Such data are now available for influenza antivirals and should be analyzed by the CDC to evaluate the accuracy of its recommendations.
Prospective Trials
Independently funded clinical trials should be conducted addressing evidence gaps and ensuring high-quality data underlie the formulation of public health recommendations. Given the large number of patients who are infected with influenza every season, it should be easy to recruit patients for large randomized trials that assess even rare events. The CDC could fund this, as could any other agency with a public health mission involving the control of influenza.
Conflict Of Interest Disclosures
The CDC should be held to the same standards as investigators and physicians and publicly disclose potential conflicts of interest held by the agency and its individual members, as is required of its external advisory committee members. For example, the CDC influenza website does not disclose that it received a $198,000 grant from Roche that was directed to the CDC's "Take 3" campaign. Such disclosure is essential to the CDC upholding its mandate as an independent, objective arbitrator of health information.
Patient-Centered Guidelines
CDC recommendations are developed through the federal advisory committee process and do not include input from patients and general physicians — the two groups most affected by and involved with yearly influenza illness. It bears remembering that influenza is not an "expert" disease, but a common one with as many as 5-20 percent of Americans symptomatic each year, according to CDC. As such, physicians have valuable experience to contribute and diverse patient groups will have varying preferences around the benefits and harms of influenza antivirals. The CDC should give general physicians and patients a seat at the table in developing its priorities and approach for influenza management.
This year, we should greet the end of the influenza season with a resolution to reevaluate current recommendations for the use of influenza antivirals. The public deserves government recommendations designed under a transparent process that fully leverages emerging opportunities in open data and promises to strengthen our ability to make evidence-informed public health decisions.
Authors' Note
Kenneth Mandl and Florence Bourgeois declare no competing interests. Peter Doshi is a co-recipient of a UK National Institute for Health Research grant for the Cochrane review discussed in this article (HTA – 10/80/01 Update and amalgamation of two Cochrane Reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children). This review focused on oseltamivir, manufactured by Roche, and zanamivir, manufactured by GSK. Doshi also received €1500 from the European Respiratory Society in support of his travel to the society's September 2012 annual congress in Vienna, where he gave an invited talk on oseltamivir. Peter Doshi gratefully acknowledges the American Association of Colleges of Pharmacy for its funding support ($10,000) for a study to analyze written medical information regarding the possible harms of statins. AACP had no involvement in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of this manuscript. Doshi is also an associate editor of The BMJ and an unpaid member of the IMEDS steering committee at the Reagan-Udall Foundation for the FDA, which focuses on drug safety research.
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