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Carl J Heneghan 1,*, Igho Onakpoya 1, Mark A Jones 2, Peter Doshi 3, Chris B Del Mar 4, Rokuro Hama 5, Matthew J Thompson 6, Elizabeth A Spencer 1, Kamal R Mahtani 1, David Nunan 1, Jeremy Howick 1, Tom Jefferson 7

1 Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
2 School of Population Health, The University of Queensland, Brisbane, QLD, Australia
3 Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore, MD, USA
4 Centre for Research in Evidence-Based Practice (CREBP), Bond University, Robina, QLD, Australia
5 Japan Institute of Pharmacovigilance, Osaka, Japan
6 Department of Family Medicine, University of Washington, Seattle, WA, USA
7 The Cochrane Collaboration, Rome, Italy
* Corresponding author Email: carl.heneghan@phc.ox.ac.uk

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Responses to this report

 

Response by Dr Larry D Sasich on 5 May 2017 at 11:04 AM
Comments on the Systematic Review and Meta-Analysis of Regulatory and Mortality Data for Zanamivir (Relenza) and Oseltamivir (Tamiflu)

The authors of a new review of the neuraminidase inhibitors zanamivir (Relenza) and oseltamivir (Tamiflu) found that these drugs minimally shorten the duration of influenza-like illness by about a day and that oseltamivir did not affect the number of hospitalizations. [1] The new review [1] confirmed a previous review done by many of the same authors in 2014 [2] and the FDA’s definitive reviews of these drugs done in 1999 that allowed for the legal marketing of zanamivir and oseltamivir in the US. [3,4] Publically available FDA documents showed that the time to improvement in major influenza symptoms with these drugs was minimal and an approval for reducing the bacterial complications of influenza was never granted for either drug.

 

The authors of the new review acknowledge a lack of experience in reviewing regulatory documents that can be daunting for new users of FDA regulatory materials because of their quantity and complexity. [1] To avoid missing important information, the authors have modified their methodology, citing the Cochrane processes used in their previous review as being inadequate. Trial analyses are now integrated by regulatory comments. [1,2]

 

A key point, particularly on the question of the efficacy of oseltamivir in reducing bacterial complications of the flu, is that the European Medicines Agency (EMA) and the US Centers for Disease Control and Prevention (CDC) came to differing conclusions from the FDA, all based on the same trials according to the new review. [1] This does not appear to be the case, as data were never submitted to the FDA supporting a reduction in bacterial complications of influenza in those using oseltamivir. The decision to submit data to support a new drug or new use approval is a business decision. Generally, the FDA requires Randomized Clinical Trials (RCT) for approval of new drugs and new uses of a drug. A possible explanation for these conflicting conclusions is that EMA and the CDC accept less rigorous evidence than the FDA.

 

Several examples of important publically available information missed in this new review are:

 

1. The 1998 Statistical Review of zanamivir in which the FDA reviewer, from independent analyses, recommend against approval of the drug based on the results of the largest of three clinical trials submitted in support of the approval of this drug. [5] The authors mischaracterize FDA statistical reviews as “re-run of statistical analyses”. The FDA’s Center for Drug Evaluation and Research’s Office of Biostatistics is extensive and staffed with doctoral educated statisticians who often do not accept sponsors’ statistical analyses on their face and produce their own reports. See http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm166250.htm.

 

2. Minutes of the February 24, 1999 FDA public Antiviral Drug Advisory Committee on zanamivir. This outside advisory committee voted 13 to 4 recommending against the approval of zanamivir based on efficacy concerns. [6]

 

3. Oseltamivir Approval Package Division Director Memo indicates that the sponsor did not submit data in their New Drug Application on the effectiveness of the drug in preventing complications due to influenza such as hospitalization, secondary bacterial infections, or mortality.[7 ]

 

Reviewing FDA documents can be formidable because of their complexity and they are written in dense regulatory jargon. Experience and familiarity with FDA regulations and documents can be an asset in the effective timely use FDA regulatory documents. For example, the neuraminidase reviews [1,2] also confirmed the conclusions of a drug newsletter written specifically for consumers published in 1999. These newsletter articles were based on publically available FDA documents just as the neuraminidase inhibitor reviews and advised the public not purchase zanamivir or oseltamivir because of their minimal effect on shortening the duration of flu symptoms and in the case of oseltamivir that there is no evidence that the drug reduces the bacterial complications of influenza. [8]

 

Accessing FDA documents and approved professional information may prevent consumers from being exposed to minimally effective drugs and drugs with significant safety concerns. This may have important implications for local health systems and national health care budgets, especially in low and middle-income countries.

 

References

 

1. Heneghan CJ, Onakpoya I, Jones MA, Doshi P, Del Mar CB, Hama R, et al. Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data. Health Technol Assess 2016; 20(42).

 

2. Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ. 2014-04-09 23:05:49 2014; 348: g2545.

 

3. United States Food and Drug Administration. Relenza (Zanamivir) Drug Approval Package, July 26, 1999. At http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21036.cfm. Accessed June 5, 2016.

 

4. United States Food and Drug Administration. Tamiflu (Oseltamivir) Drug Approval Package, October 27, 1999. At http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21087_Tamiflu.cfm. Accessed June 5, 2016.

 

5. Elashoff M. United States Food and Drug Administration Statistical Review Relenza (Zanamivir), December 1998. At http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/021036-stats.pdf. Accessed June 6, 2016.

 

6. United States Food and Drug Administration Center for Drug Evaluation and Research. Summary Minutes Antiviral Drugs Advisory Committee, February 24, 1999. At http://www.fda.gov/ohrms/dockets/ac/99/meeting/3496m1.pdf. Accessed June 6, 2016.

 

7. Jolson HM. United States Food and Drug Administration, Division Director Memo http://www.accessdata.fda.gov/drugsatfda_docs/nda 99/21087_Tamiflu_medr_P1.pdf. Accessed March 4, 2015.

 

8. Public Citizen Health Research Group. No Not Use Zanamivir (Relenza) for the Flu – Cost Without Benefit and Do Not Use Oseltamivir (Tamiflu): Another Expensive New Flu Drug, 1999. At http://www.citizen.org/hrg/NEWSLETTERS/flutext.htm. Accessed June 6, 2016.

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