BMJ Open Data Campaign

Open letter to Roche about oseltamivir trial data

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e7305 (Published 29 October 2012)
Cite this as: BMJ 2012;345:e7305

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Please could someone tell me why the ethics committees approve studies without any guarantee they will be published, or at least the raw data placed in the public domain?

Would this go a long way to reduce publication bias?

Kind regards
David L.

Competing interests: None declared

John d. Leopold, Physician

Cwmrhydycwrw Cottage Hospital, Swansea sa6 4nl

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We have good reason to share the emerging concerns about the financial and public health cost of Governments maintaining their Tamiflu orthodoxy during the H1N1 outbreak in the face of evidence demonstrating the indefensibility of such a position. The insistence on managing ‘England as a single epidemiological unit’ [1], and maintaining the ‘containment’ phase beyond any rationality led directly to perverse, expensive and ultimately ineffectual interventions.

The mass chemotherapy response of the UK Government to the H1N1 outbreak was entirely without precedent [2] and the mechanics of its imposition contrary to the evidence. Sandwell, a modest urban municipality, used the best evidence available to ensure that Tamiflu was only administered where clinically justified including in a clinical risk group, contact with a case, and able to start treatment within 48 hours [3]. This was an enormous logistical enterprise but staff were motivated by ‘doing the right thing’ in the right way. This evidence based response was swept away without consultation and replaced by the centrally imposed, misguided and opportunistic largesse of the national on line Tamiflu free for all; a decision with taken with no respectable evidence of effectiveness.

Many of us in PCTs considered our role to have been transformed from front line public health to that of an NHS delivery system for the pharmaceutical industry. Anti-viral collection centres doubled as publicly funded venues for protracted ‘pox parties’ enticing hundreds of cases and contacts to share a relatively confined space. There is growing evidence that flu can be spread through sub-clinical cases, creating the potential for any assembly of the public to spread the infection [4, 5]. This should be the major control consideration for planning to prevent pandemic spread in future. Our views (and we understand we were not alone in raising these concerns) expressed at the time to the Department of Health were ineffectual.

It is one thing to make compromises between public and political expectations when the evidence is uncertain It is quite another to collude with a disregard for the evidence despite legitimate and informed objections.

[1] Chambers J, Barker K, Rouse A. Reflections on the UK’s approach to the 2009 swine flu pandemic: Conflicts between national government and the local management of the public health response. Health Place 2012; (18): 737–745.
[2] Ellis C, McEwan R. Editorial on use of antivirals. BMJ 2009; 339: 2639.
[3] NHS National Institute for Health and Clinical Excellence Technology appraisals TA158, September 2008. http://www.nice.org.uk/guidance/TA158 last accessed 17th December 2012.
[4] Centers for Disease control. Additional Information about Vaccination of Specific Populations. Influenza Prevention and Control Recommendations. Published for the 2010-11 Influenza Season; Adapted for the 2012-13 Influenza Season http://www.cdc.gov/flu/professionals/acip/specificpopulations.htm last accessed 17th December 2012.
[5] Chao D-Y, Cheng K-F, Li T-C, Wu T-N, Chen C-Y, et al. Serological Evidence of Subclinical Transmission of the 2009 Pandemic H1N1 Influenza Virus Outside of Mexico. PLoS ONE 2012; 6(1): e14555. doi:10.1371/journal.pone.0014555

Competing interests: None declared

Patrick J Saunders, Consultant in Public Health

John Middleton, Anna Pronyszyn, Mary Tooley, Michele Lawrence, Claire Parker

Sandwell PCT, Kingston House, High St, West Bromwich, B70 9LD

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Godlee’s appeal to Sir John Bell, ‘as an internationally respected scientist and clinician and a leader of clinical research in the UK to bring your influence to bear on your colleagues on Roche Board,’ is to be welcomed. But we fear her request will be ignored, as was Sir Ian Chalmers' in 2007 [1].

There are few arguments that can be made for withholding clinical trial data, and they are potentially strongly influenced by conflicts of interest. One is an ethical issue over patient confidentiality; the second is that disclosure leads to patient harm.

The pharmaceutical industry understands well the potential influence of academics, and rewards can be substantial. For example, according to Roche's 2011 Financial Report, Sir John received Swiss Fr 390,000 ($420,000) last year for his role on the Board of Directors. [2] The question is what do Roche and its shareholders expect for this level of involvement and level of remuneration? And, in what ways could this role help to actually facilitate the kind of scientific scrutiny that the Cochrane group are now attempting to apply to trial data for the antiviral drug oseltamivir, by helping to ensure that Roche honours its commitments to allow access to this data?

The proponents of trial non-disclosure often quote the harms that could be caused. Yet, actual reports of harms are hard to identify in the literature. In contrast, there are substantial benefits from open disclosure. As an example, in the Antithrombotic Trialists' Collaboration, 287 different studies contributed patient level data to the effects of antiplatelet therapy for patients at high risk of occlusive vascular events [3]. Moreover, vast databases such as the Clinical Practice Research Database and the National Joint Registry routinely use patient level data to inform practice: why is it therefore proving so difficult to obtain clinical trial data?

The substantial 'speaker fees' that many clinicians and clinical academics receive (upwards of $100,000 in some cases), has prompted some public universities in the USA to propose banning such activities given the potential for conflicts of interest and their influence on policy and practice [3]. Many of these have only come to light following new rules in the US that encourage pharmaceutical companies to publicly disclose all fees (over $10) paid to academics [4]. These measures are important, given the evidence that financial relationships can influence the results of scientific studies [5].

The European Medicines Agency and the BMJ are making great strides in improving access to clinical study data, to ensure that practice is based on transparent evidence. Yet, many manufacturers and clinical academics are clearly uneasy with proactive disclosure of data and financial relationships. At a time when the pharmaceutical Industry wants stronger ties with academia, there is a need for greater scrutiny.

We suspect many colleagues in clinical academia share our views, and we look forward to moving the debate forward to a place where we can develop a more transparent and conflict-free policy towards accessing data.

Matthew Thompson, Clinical Reader, University of Oxford
Carl Heneghan, Clinical Reader, University of Oxford

[1} Open letter to Roche about oseltamivir trial data. Chalmers I http://www.bmj.com/content/345/bmj.e7305/rr/613849
[2] Roche Finance Ltd. Finance Report 2011, page 162. http://www.roche.com/investors/annual_reports/annual_reports_2011.htm accessed on December 2nd, 2012
[3] Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Antithrombotic Trialists' Collaboration. BMJ 2002;324:71
[4] Oregon Health & Science University may ban faculty from pharmaceutical industry speakers' bureaus. http://www.oregonlive.com/health/index.ssf/2012/11/oregon_health_science... accessed Dec 2nd, 2012
[4] Disclosing pharma payments to oncologists: what will we learn? Burstein HJ. J Natl Compr Canc Netw 2012;10:133-134
[5] Scope and impact of financial conflicts of interest in biomedical research: a systematic review. Bekelman JE, Li Y, Gross CP. JAMA 2003;289:454-65

Competing interests: Matthew Thompson and Carl Heneghan receive grant funding from the National Institute for Health Research for the update and amalgamation of Cochrane Reviews on neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Their full conflicts can be viewed on their respective University biographies (http://www.phc.ox.ac.uk/team).

Matthew J Thompson, Clinical Reader

Carl Heneghan

University of Oxford, New Radcliffe House, Woodstock Road, Oxford, OX2 6GG

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These articles reminded me of a picture I took when I had paused the film Elf a couple of years ago during the "stockpiling" of oseltamivir. He was only having blood taken for paternity testing! Is this subliminal advertising which families are likely to watch each Christmas?

Competing interests: None declared

Martin R Toynbee, General Practitioner

Mid Sussex Health Care, The Health Centre, Lewes Road. Ditchling

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9 November 2012

Fiona Godlee has asked Sir John Bell, Regius Professor of Medicine at Oxford University and the only medically qualified member of Roche’s board, to use his influence to persuade the company to release data needed to judge whether the massive purchases of its drug Tamiflu represent a justified use of public funds.

Six years ago, when Sir John was President of the Academy of Medical Sciences, I spoke and wrote to him about biased under-reporting of medical research.

My letter of 12/10/06 (see text below) referred to the lack of scientific and ethical leadership to confront those form of unethical and unscientific conduct, and asked him to clarify the Academy’s position.

Having not received a response several months later, I asked Sir John when I might expect a reply.

He said that he might have mislaid my letter and asked me to send him a copy, which I did on 15 June 2007. I am still waiting for a reply.

This dismissive attitude to a form of scientific misconduct which has been shown to result in the avoidable suffering and deaths of patients, as well as wasted resources, does not reflect well on the leadership of the medical research community.

Competing interests: None declared

Iain Chalmers, Coordinator

James Lind Initiative, Oxford OX2 7LG, UK

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European governments should sue Roche

At an open seminar arranged by Health Action International (Europe) on 12 October about access to medical research data, I asked why European governments had not sued Roche to get the money back they had spent on needlessly stockpiling Tamiflu. Roche has withheld data that purports to show that Tamiflu has dramatic effects. We all wonder why it is so difficult to get these data from Roche and why Roche has not published them, if it is really true that they show these effects.

None of those present at the seminar could explain why our governments have not sued Roche but another speaker told me in private that the likely reason is that they don't want to lose face. Well, it's better to lose face than lose billions of taxpayers' money I think. As far as I can work out, Tamiflu is likely not any better than paracetamol. The FDA required Roche to print a disclaimer on the lables: "Tamiflu 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" (1). When the FDA first reviewed a similar drug, zanamivir (Relenza) from GlaxoSmithKline, the advisory committee recommended that the drug should not be approved. Zanamivir was no better than placebo when the patients were taking other drugs such as paracetamol. However, FDA overruled the committee, probably for political reasons. When that was done, FDA also had to approve oseltamivir later the same year (2).

European governments should sue Roche, which might also have the effect that the hidden trial results come out in the open. Furthermore, I suggest we boycott Roche's products until they publish the missing Tamiflu data.

1 Doshi P. Neuraminidase inhibitors: the story behind the Cochrane review. BMJ 2009;339:b5164.
2 Cohen D, Carter P. WHO and the pandemic flu 'conspiracies.' BMJ 2012;340:c2912.

Competing interests: None declared

Peter C Gøtzsche, Professor

Nordic Cochrane Centre, Rigshospitalet

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