Tamiflu: the battle for secret drug dataBMJ 2012; 345 doi: https://doi.org/10.1136/bmj.e7303 (Published 29 October 2012) Cite this as: BMJ 2012;345:e7303
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The spectre here leads to the broader need to debate whether in the business of drug manufacturing (designed for the public) the manufacturer should in part or in whole be its own policing agent or be fully bound by law to 'public' policing using public portfolios trained for the role.
To any simple mind like mine, settling for self-policing seems like also settling for avoidable public health disaster.
And to leave the extent of disclosures of actionable data base by drug manufacturers to 'self honour' (promise) is to assume an invulnerability of the mind to self-preservatory finagling when such seems expedient; either to stay ahead of rivals or to suppress/hide statiscal indecencies that point away from profit interest.
Reputation can mislead; based purely on past efforts rather than current endeavours.
Excellence on the other hand, is an ongoing journey towards quality targets about which nobody would wish to hide details where patency laws are alive and well to safeguard earned monopolies.
The efforts by BMJ and its fellow crusaders are headed in the right direction both for their own continuing reputation, excellence and relevance but more importantly for the safe umbrella those efforts might provide for an otherwise vulnerable public in the murky waters of profit oriented drug manufacturing.
To be an accomplice in a drug use culture where patients are paying for what is effectively not more than placebos, or the harm of which will be found out only thro 'adverse effects' reporting (that is, retrospectively)
is neither befitting for the guardians of the system (such as BMJ or equivalents ought to be) nor safe for the very public already besieged by germs/ viruses and distrust.
The road to victory, the type BMJ and consumers deserve, seems more destined to pass through parliaments rather than thro the self platitudes and nonexistent self honour of drug manufacturers whose profit motives have never been hidden from the public and to which anything else is mere serendipity.
Profit motives are never hidden and so also must they not be allowed to hide their scientific evidence for the claims they wish to sell to the public.
Increasingly the world of drug manufacturing and its commercial underpins is more and more a stiffly competed world with blue oceans rapidly turning red from predatory rivalries.
It is only fair then to design a situation where the demands for releasing data into independent hands does not amount to hamstringing the manufacturers within a red ocean in which by their cooperation, they submit to suicidal positions within surging cannibalistic currents where it doesn't take much to be eaten up by fellow sharks.
Therefore as we seek to protect the public via righteous vigilance and campaigns, we must no less protect the invested energies of manufacturers by righteous steps to keep them safe from murderous vulnerability in the only market inside which they have chosen to pitch a stake.
Protecting legitimate concerns on both sides without wittingly or unwittingly 'gaming' the enterprise on either side is the best and only win-win way forward. Any one undermining such tack deserves nothing but the hammer.
As a busy clinician who slaps a bill on every patient that visits, it is important that one's conscience is clean that money paid by the sick for cure is not spent serving them chalk served as cheese.
Roche should be willing to submit all its cheese for scrutiny one its legitimate non selfish concerns are addressed.
In the big picture of things, to do otherwise will amount to being penny wise and pound foolish.
Competing interests: No competing interests
Tinnemann P , Spelsberg A , Jonitz G , Antes G , Wodarg W , Keil U
On September 6, 2012, an unprecedented coalition of EBM and public health scientists, the chamber of physicians of Berlin, the anti-corruption organization Transparency International and the Charité Universitätsmedizin Berlin invited Peter Doshi from Johns Hopkins University School of Medicine, to present his research on the science and policy of pandemic influenza and influenza antivirals . Doshi, a reviewer for the Cochrane Collaboration systematic review on neuraminidase inhibitors, argued that influenza is a disease that has been understood primarily through the marketing efforts of public health professionals, and that there are major problems in the evidence base for influenza vaccines and antivirals. Doshi noted that prior to 2009, around $8 billion worth of oseltamivir (Tamiflu) was stockpiled by governments in preparation for an influenza pandemic with assumptions about the proven effectiveness of the drug, but those assumptions remain unproven. Doshi asked how this could happen in a world in which public health decision is believed to be science-based.
In front of clinicians, EBM and public health scientists, Doshi used original policy documents by the World Health Organization (WHO) , , ,  and other national pandemic plans , , to show that claims made about viral pandemic threats and their control through preparedness measures including mass vaccination and the stockpiling of antiviral agents such as oseltamivir were all but evidence-based. Documented close ties between members of the Emergency Committee of WHO, which was responsible for declaring a pandemic and for decision-making during a pandemic, and the pharmaceutical industry only added to the lack of trust in the objectivity and independence of official decision-making structures  .
Doshi highlighted the complete absence of public health bodies carrying out an independent review of the oseltamivir evidence base prior to stockpiling. Instead of examining the data themselves, influential bodies such as the US Department of Health and Human Services and the Centers for Disease Control and Prevention (CDC) pointed to industry authored publications in medical journals—in particular, one non-systematic review published in 2003 in Archives of Internal Medicine .
However, this study, a pooled analysis of ten randomized controlled trials of which eight remain unpublished, was later shown to be seriously flawed. Oseltamivir’s manufacturer, Roche, also admitted some of its published studies were ghostwritten.
Doshi explained how their Cochrane team led by Dr. Tom Jefferson in Rome, concluded that journal publications were unreliable, and instead decided to base their systematic review upon far more detailed documents called Clinical Study Reports. After requesting these reports from the European Medicines Agency (EMA) under its new freedom of information policy (2010), the Cochrane investigators were able to compare the reports (more than 22,000 unique pages), submitted to EMA by Roche for marketing approval of oseltamivir in 2002, with the published results appearing in prestigious medical journals. This revealed large inconsistencies between the published information and the previously secret internal company reports.
Of public health relevance, the Cochrane team found no evidence for a preventive effect on spread of the virus or decreased risk of severe complications like hospitalization. (Incidentally, the U.S. Food and Drug Administration (FDA) arrived at the same conclusions in 2000, and in fact language documenting the lack of evidence was inserted into the US product labeling). Even more disquieting: despite publicly promising to release full study reports, Roche has kept the study protocols and the bulk of its study reports afar from public scrutiny.
Without the EMA’s new policy on access to documents, independent scientists would not be able to access these detailed data. But Doshi noted that reports EMA provided the Cochrane team were themselves incomplete because EMA itself had not requested the full reports from Roche.
Obviously, selective reporting, attrition and publication bias are well known problems in the world of medical publishing, and have partially been addressed by mandatory prospective registration of clinical trials worldwide. However, the amount of pharmaceutical industry data and information in relation to oseltamivir kept inaccessible to independent review, was astounding even to experienced researchers in this particular field like Jefferson and Doshi.
The conclusion of the public debate following Doshi’s presentation was straightforward: selective reporting, and the omission or suppression of data, may be routinely utilized, unintentionally or intentionally, concealing an accurate understanding of a study. Those relying on evidence-based medicine need to urgently question whether current established EBM methods of evidence appraisal, focussing on journal publications, are able to distinguish distorted clinical trial results from valid findings. In fact, the validity of EBM and related guidelines, as long as they are solely based on publications in peer-reviewed journals (or other data inaccessible to independent scrutiny), must be questioned and put under review.
Calls were made to urgently address this problem. Should it be left to the scientific community, publishers or even to the for-profit industry? What should be done if intentional selective reporting is used for individual gains or economic benefits, and which preventive actions or sanctions, respectively, against such abuses should be implemented?
The oseltamivir story raised deep questions about the accuracy and integrity of decisions of regulatory agencies and public health bodies. Officers from regulatory agencies in attendance of the debate claimed that governmental institutions are uniquely positioned to ensure the objective assessment of and recommendations about medical interventions for the well-being of the population. However, the case of influenza and oseltamivir reveals that additional control mechanisms are necessary to prevent regulatory or public health agencies from ignoring concerns  of independent scientists and civil society organizations. Even the FDA’s official “Warning Letter” to Roche in the year 2000, stating that Tamiflu has not been shown to reduce serious complications of influenza  was apparently totally ignored by those in other parts of the government who made the decision to stockpile the drug, citing Roche-authored publications as the scientific “evidence” to support claims that oseltamivir would reduce complications and hospitalizations .
It was suggested that the first and most publicly relevant measure should be the urgent revision of public health recommendations such as the international and national pandemic influenza plans, and secondly, to stop stockpiling of a drug still unproven to prevent the spread of influenza or its complications.
Finally, a democratic and transparent control mechanism for regulatory and public health agencies and related expert committees is urgently needed. A call for public financing of research in the public interest and with unhindered access to complete datasets for independent scientific evaluation, evolved in the debate as the only possible way forward to allow objective analysis and unbiased publication of clinical trial results.
It was acknowledged that the recent efforts by EMA regulators to provide access to documents in their possession (including those submitted by industry, such as Clinical Study Reports and study protocols)  were a huge step forward towards ensuring transparency in medical research.
For spreading the debate in the wider medical and scientific community, as well as to gain broader public support, the authors have drafted the “Berlin Declaration 2012” - together with a signing list - aiming to promote and reinstitute the integrity of scientific publishing, EBM and public health decision making.
 Ärztekammer Berlin. http://www.aerztekammer-berlin.de.
 Transparency International Deutschland e.V. http://www.transparency.de
 Documentation accessible at
 Pandemic influenza preparedness and response. A WHO guidance document. Geneva, World Health Organization, 2009.
 WHO global influenza preparedness plan. The role of WHO and recommendations for national measures before and during pandemic. Geneva, World Health Organization, 2005 (WHO/CDS/CSR/GIP/2005.5).
 Influenza pandemic plan. The role of WHO and guidelines for national and regional planning. Ge¬neva, World Health Organization, 1999 (WHO/CDS/CSR/EDC/99.1).
 WHO guidelines on the use of vaccines and antivirals during influenza pandemics. Geneva, World Health Organization, 2004 (WHO/CDS/CSR/RMD/2004.8).
 Robert Koch Institut. Influenzapandemieplan, Teil I, II, III, Anhang; 15.05.2007. http://www.rki.de/DE/Content/InfAZ/I/Influenza/Influenzapandemieplan.html, accessed September 22, 2012
 WHO 2011. Comparative analysis of national pandemic influenza preparedness plans.JANUARY 2011
http://www.who.int/influenza/resources/documents/comparative_analysis_ph..., accessed September 22, 2012
 WHO Pandemic influenza preparedness Framework for the sharing of influenza viruses and access to vaccines and other benefits. http://whqlibdoc.who.int/publications/2011/9789241503082_eng.pdf, accessed September 22, 2012
 Jefferson, Tom, Mark A Jones, Peter Doshi, Chris B Del Mar, Carl J Heneghan, Rokuro Hama, und Matthew J Thompson. 2012. „Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children“. Cochrane database of systematic reviews (Online) 1: CD008965. doi:10.1002/14651858.CD008965.pub3.
 Council of Europe, Strasbourg, January 26,2010: The handling of the H1N1 pandemic: More transparency needed? http://www.coe.int/t/dc/file/events/2010_H1N1_/default_en.asp.
 Epstein H. Flu Warning: Beware the Drug Companies! The New York Review of Books [Internet]. 2011 May 12 [cited 2011 Jun 17]; Available from: http://www.nybooks.com/articles/archives/2011/may/12/flu-warning-beware-...
 Keil U, Schönhöfer P, Spelsberg A. The invention of the swine flu pandemic. Eur J Epidemiol 2011;26:187-190
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 Doshi P. Jones M and Jefferson T. Rethinking credible evidence synthesis. BMJ 2012;344:d7898doi:10.1136/bmj.d7898
 Tröger, U; Bode-Böger, S M. The Place of Neuraminidase Inhibitors in the Prophylaxis and Treatment of Influenza Dtsch Arztebl Int 2006; 103(51-52): A-3486
 Doshi P, Jefferson T, Del Mar C. The imperative to share clinical study reports: recommendations from the Tamiflu experience. PLoS Med 2012;9(4):e1001201.doi:10.1371/journal.p.med.1001201
 Kurth R, Buchholz H, Haas W. Antivirals are not a magic solution but an important tool in planning for pandemics. Dtsch Ärztebl Int 2006;103(51-52):A3484-5
 Centers for Disease Control and Prevention: 2 011-2012 Influenza Antiviral Medications http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm, accessed September 15, 2012
 Food and Drug Administration (FDA) April 4, 2000. Warning Letter to Roche. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati...
 Doshi P and Jefferson T. Drug Data Shouldn’t Be Secret. Published: April 10, 2012 .http://www.nytimes.com/2012/04/11/opinion/drug-data-shouldnt-be-secret.html, accessed October 31, 2012.
 Eichler H-G, Abadie E, Breckenridge A, Leufkens H, RAsi G. Open clinical trial data for all? A view from regulators. PLoS Medicine 2012; 9(4):e1001202.doi:10.1371/journal.pmed.1001202
Competing interests: No competing interests