Tamiflu: 14 flu seasons and still questions

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f547 (Published 25 January 2013)
Cite this as: BMJ 2013;346:f547

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To the editor

The valid concern about the effectiveness of oseltamivir [1] is particularly pertinent to the management of influenza outbreaks in aged care facilities (ACFs). In many developed countries, guidelines recommend the prophylactic use of antivirals in confirmed institutional influenza outbreaks however there is very limited high quality publicly available data to support this practice.

Until recently the only randomised controlled trial data from the aged care setting found that seasonal prophylaxis with oseltamivir had no significant impact on overall laboratory-confirmed influenza but reported a significant reduction in symptoms [2].

The recent paper by Booy et al [3] was a welcome addition to this field, but given the limited existing evidence base, it is particularly important that any study qualifications are carefully considered.

The use of oseltamivir for both treatment and prophylaxis (T&P) in confirmed ACF influenza outbreaks was reported to significantly reduce outbreak duration and attack rate in comparison to use of oseltamivir for treatment only (T). The authors concluded that the trial provided “some support for a policy of treatment and prophylaxis with oseltamivir in controlling influenza outbreaks in ACFs”. However, differences in deaths, hospitalisations and pneumonia were not significant. Popular medical media have lauded the work as a “landmark study” and reported that the “results provide good evidence to support an active policy of treating and preventing influenza promptly, once an outbreak is declared” [4].

Unfortunately the underpowered nature of this study, with just three facilities randomised to T and six to T&P, meant that a single outbreak could substantially impact on the results.

Indeed, inclusion of a particular T outbreak (Facility B) seriously limits the interpretation of this study. Data from the paper and subsequently provided by the authors, indicated that the time from first influenza-like illness (ILI) case to intervention commencing was approximately 20 days, at which time there were already 22 ILI cases in the facility. Treatment was provided to fewer than half the ILI cases and the intervention was subsequently changed to T&P after about 10 days. In contrast, the mean time from first ILI case to outbreak intervention was 12.7 days in T facilities overall and 5.0 days in T&P facilities.

The unusual nature of the outbreak in Facility B and its management dictate that the analysis is repeated excluding this facility. It appears that the reported difference in outbreak duration would be non-significant if facility B was excluded, providing important qualification to the study conclusions. Differences in hospitalisations and deaths would be further reduced and remain non-significant.

The evidence base for guiding antiviral use in ACFs remains limited. In the absence of further compelling trial data from Roche, there is a need for additional adequately powered research before firm recommendations can be made.

Tony Merritt
Public Health Physician
Hunter New England Population Health

David Durrheim
Professor of Public Health Medicine
University of Newcastle, Australia

References
(1) Krumholz HM, Jackevicius CA, Ross JS. Tamiflu: 14 flu seasons and still questions. BMJ 2013;346:f547.
(2) Peters PH Jr., Gravenstein S, et al. Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population. Journal of the American Geriatrics Society 2001 Aug;49(8):1025-31
(3) Booy R, Lindner R, Dwyer DE, Ying M. Treating and preventing influenza in Aged Care facilities: a cluster randomised controlled trial. PLoS ONE Open Access Online 7(10): e46509. 2012.
(4) A new approach to deadly influenza outbreaks in nursing homes. 18 October 2012. [Cited 19 January 2013]. Available from URL http://www.healthcanal.com/infections/33099-new-approach-deadly-inflenza...

Competing interests: None declared

Tony D Merritt, Public Health Physician

Hunter New England Population Health, Locked Bag 10, Wallsend, NSW 2287 Australia

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The suggestion of putting the responsibility to publish on the sponsoring company, rather than the investigator, certainly has merit. I think this could certainly be a good idea for studies both sponsored and managed by a company, where it is clear that the company has responsibility to publish. In those cases, I would wholeheartedly support Edwards's suggestion.

However, that won't cover all studies.

What about investigator-led studies, where the pharma company simply provides funding, but the study conduct is the responsibility of the investigator? Wouldn't it be up to the investigator to publish in that case?

And what about studies that are not sponsored by a pharmaceutical company? I suppose the idea could be extended to other funders, such as the MRC. If the MRC were to have unpublished studies, then no more ethical approval for any more MRC funded studies until those previous ones get published.

Although again, the fairness of that suggestion would depend on where the responsibilities lie. Is it the responsibility of the researcher or the funding body?

And then what about studies not funded by major bodies, but just funded out of departmental budgets? If they are not published, do we penalise just the researchers, the whole department, or the whole institution?

I agree with Edwards there is more that RECs could be doing here, and hope that they will have the procedures in place to take a more active role in enforcing completeness of publication soon, but when you start to look at the details, it soon becomes clear that it's quite complex.

Competing interests: As stated previously

Adam Jacobs, Director

Dianthus medical Limited, London, SW19 2RL

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Adam Jacobs fears that RECs may not be able to enforce the type of up-front commitments to publish that I recommend by means of an agreed, boiler plate, non-negotiable statement.

His blog clarifies why he has difficulties. He imagines the commitment to publish is made by the individual academic researcher. In fact, I view the committment as being required by the pharma company which is funding the research.

If the company has not, one year after ending the study, made the publication arrangements it agreed to (to the REC which gave the original approval, on this basis), then the REC should be duty bound to alert the HRA.

The HRA should then send out a notice to all RECs that pharma company X is in breech of its agreement. New studies by company X would be blocked, and existing studies would be recommended for review and possible suspension.

Janet Wisely, on behalf of the HRA, may already be moving in this direction, having earlier written to the BMJ stating:

"We will do this (ensuring compliance) by routinely reviewing the final report to identify any failure to comply with researchers' declared intentions to publish, register or make study information or tissue available one year after the final report. We are currently exploring how best to implement these improvements and safeguards, and expect to establish a new system early in 2013."

Let my recommendation to the HRA be clear:

1. Specifiy what you want the initial commitment to say. Make it as watertight as possible. Make it part of the REC Standard Operating Procedure (in the handbook).

2. Make compliance a matter explictly for the pharma company in CTIMS trials.

3. Make explicit the sanctions the HRA will enforce, and make them onerous.

Competing interests: None declared

Alan S Edwards, Retired Company Director

Essex Research Ethics Committee, Downham

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29 January 2013

Edwards makes some good points about the role of RECs. They are indeed in a powerful position, and could play an important part in the fight against incomplete publication.

However, I think it's a bit more complex than Edwards says. Ethics committees can certainly require a commitment to publish (and on my committee, we already do), but the problem is what RECs can do about it if that commitment is not honoured. At the time a study is approved, there is no way to know whether the commitment will be met.

A system based on whether applicants have published their previous studies would be needed if the system were to be effective. I have previously written a blogpost explaining my thoughts on this in more detail.

It's also worth reading a previous BMJ response from Janet Wisely on this topic.

While it's not a straightforward matter for RECs to police completeness of clinical trial publications, I do actually think the problems are solvable, and am reasonably optimistic that RECs will soon be doing more in this area. Watch this space.

Competing interests: My company provides services to both pharmaceutical companies and academic researchers to help them get their trials published. I am a member of an NHS REC.

Adam Jacobs, Director

Dianthus medical Limited, London, SW19 2RL

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It seems to me that RECs have a uniquely powerful opportunity to enforce a much higher publication rate by pharma companies than other entities (such as Medical Journals).

This is because RECs hold the gateway to trials with patients that the pharma companies badly want -- RECs have a very strong bargaining position.

And yet RECs seem very unwilling to step up to their responsibilities, viewing themselves too much as a David facing a Goliath.

Among the excuses I hear for RECs shying away from action are reasonable practical ones: no-one can ensure publication, and arbitrary cut off dates may need extensions for legitimate reasons. When pressed, Pharma companies will produce all sorts of plausible weasel words promising something like "best endeavours" to publish.

I would like there to be a "boiler plate" statement that RECs should require Pharma to sign up to as part of the REC approval process. Sign up (exactly) or no approval for the trial.

My own suggestion for the wording would be as follows:

"We undertake to publish the full results of this trial within one year of the ending of the trial --either in a public journal or, failing that, on our own company website.

In the event that the company has no local website, the results will be forwarded in full to the approving REC, with permission for the REC to disseminate results as it sees fit.

The date of the ending of the trial will be determined by the last interaction with a trial participant in accordance with the protocol described in the trial application."

What could possibly be wrong if all RECs were to make this a standard requirement?

Competing interests: None declared

Alan S Edwards, Retired Company Director

Essex Research Ethics Committee, Downham, Essex

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To the Editor:

Two of the 14-year-old Tamiflu questions, efficacy and reduction of influenza complications, raised by Krumholz and colleges in their January 25, 2013 editorial appear to have been substantially addressed 13 years ago in the professional product label or package insert for the drug.[1]

Regarding efficacy, this is the statement that appeared in the Clinical Studies section of Tamiflu’s November 2000 professional labeling: “…there was a 1.3 day reduction in the median time to improvement in influenza-infected subjects receiving TAMIFLU compared to subjects receiving placebo.” This same label goes on to say that: “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.”[2]

The Food and Drug Administration (FDA) Division Director’s Memo dated October 1999 noted that “… oseltamivir confers a modest clinical benefit …” and that the Tamiflu application does not contain information on the “… effectiveness in preventing complications due to influenza….”[3]

Tamiflu’s professional product label has been amended to say that in a pooled analysis of 3 clinical trials of subjects’ age 65 and older “… there was a 1-day reduction in the median time to improvement in influenza-infected subjects receiving TAMIFLU compared to those receiving placebo.”[4]

The references cited are free and publically available on FDA and US National Library of Medicine Web sites.

Tamiflu’s “modest” efficacy and that the drug has not been shown to prevent bacterial complications of influenza have been known for over a decade. A quick reading of the drug’s professional labeling should have raised questions about the enthusiasm for Tamiflu. Accessing FDA approval documents that can contain unpublished analyses and analyses of unpublished clinical trials provide additional documentation for the information provided in professional product labels.

References

[1] Krumholz HM, Jackevicius CA, Ross JS. Tamiflu: 14 flu seasons and still questions. BMJ. 2013-01-25 14:20:28 2013;346.

[2] Roche Laboratories, Inc. Oseltamivir (Tamiflu) Professional Product Label revised November 2000. At
http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/21087S002lbl.pdf. Accessed January 27, 2013.

[3] Jolson HM, Director, Division of Antiviral Drug Products. Division Director Memorandum: Oseltamivir (Tamiflu), October 25, 1999. At http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21087_Tamiflu_medr_.... Accessed January 27, 2013.

[4] Genentech Inc. Oseltamivir (Tamiflu) Professional Product Label revised December 2012. At http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ee3c9555-60f2-4f82.... Accessed January 27, 2013.

Competing interests: None declared

Larry D. Sasich, Consultant

Saudi Arabian Food and Drug Authority, Riyadh, Saudi Arabia

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