Researchers are pushing for pharmaceutical companies to make full data from their clinical trials publicly available, allowing risks and benefits of drugs to be independently analysed. Currently drug research - clinical trial data – is considered commercial confidential information, not a public, social or philanthropic interest. The researchers have documented a number of cases in which access to full trial data would “radically change public knowledge of safety and efficacy” of widely used drugs, including Vioxx and Tamiflu. The researchers point out that there is insufficient evidence that Tamiflu – stockpiled by governments around the globe in 2009, including the Australian Government, to quarantine swine flu – had any preventative effect.
REPORT: Consider the case of the influenza antiviral Tamiflu (oseltamivir). Prior to the global outbreak of H1N1 influenza in 2009, the United States alone had stockpiled nearly US$1.5 billion dollars worth of the antiviral. As the only drug in its class (neuraminidase inhibitors) available in oral form, Tamiflu was heralded as the key pharmacologic intervention for use during the early days of an influenza pandemic when a vaccine was yet to be produced. It would cut hospitalizations and save lives, said the US Department of Health and Human Services. The Advisory Committee on Immunization Practices – ACIP, the group the US Centers for Disease Control and Prevention uses to form national influenza control policy – said it would reduce the chances of developing complications from influenza. So, too, did the Australian Therapeutic Goods Administration and the European Medicines Agency.
Chris Del Mar, from the Centre for Research in Evidence-Based Practice at Bond University, and colleagues, Peter Doshi from Johns Hopkins School of Medicine and Tom Jefferson from The Cochrane Collaboration in Italy presented their argument in the peer-reviewed – PLoS – Public Library of Science Medicine journal.
“It is the public who take and pay for approved drugs, and therefore the public should have access to complete information about those drugs,” the researchers said.
Earlier this year Professor Del Mar was involved in a review of Tamiflu, which concluded that although it does reduce symptoms, there is no reliable evidence the drug reduces the complications of influenza and hospitalisations.
Del Mar says governments around the world rushed to stockpile Tamiflu largely on the basis of these claims. ”All the data we’ve seen so far suggests it’s no better than aspirin. It could be, but we don’t have the data to say so,” Professor Del Mar said. He adds the available evidence is insufficient to tell whether Tamiflu is successful in preventing influenza and stopping its transmission. Del Mar says there is far better evidence available for physical barriers such as handwashing, masks, gloves and quarantining.
Del Mar says the evidence for Tamiflu reducing hospitalisation came from a publication which summarised data from a number of trials by drug manufacturer Roche. ”It wasn’t until you scratched it a bit that you realised there was a problem,” he said.
In 2009, Del Mar and his research group sought to verify the conclusions of the published study by checking lengthy clinical study reports, which describe in detail what happened in the trials. When the first author of that study did not have the full data, Professor Del Mar and his team turned to Roche, but after two years of “extensive correspondence” they only received a fraction of the reports from the company.
Del Mar’s group then supplemented the incomplete data from Roche with reports obtained from regulators under freedom of information requests, along with leaked documents.
“This information has turned our understanding of the drug’s effects on its head,” the researchers said. ”Our review has led to the detection of numerous reporting biases and fundamental problems in trial design, and we have concluded that previous effectiveness claims were not supported by the available evidence.”
The researchers also found evidence that serious adverse events were not reported in published papers.
“The drug companies are not publishing some of the experiments they’ve done,” Del Mar said. ”Suspicious people around the world say, ‘well, it’s because those data don’t say what the drug company wants to show and will affect their shareholders’ interest’.”
Systematic reviews of published randomized clinical trials (RCTs) are considered the gold standard source of synthesized evidence for interventions, but their conclusions are vulnerable to distortion when trial sponsors have strong interests that might benefit from suppressing or promoting selected data.
More reliable evidence synthesis would result from systematic reviewing of clinical study reports—standardized documents representing the most complete record of the planning, execution, and results of clinical trials, which are submitted by industry to government drug regulators.
Unfortunately, industry and regulators have historically treated clinical study reports as confidential documents, impeding additional scrutiny by independent researchers.
We propose clinical study reports become available to such scrutiny, and describe one manufacturer’s unconvincing reasons for refusing to provide us access to full clinical study reports. We challenge industry to either provide open access to clinical study reports or publically defend their current position of RCT data secrecy.
In a statement to ABC Science Online, Roche said it stood by the efficacy and safety of Tamiflu. The drug behemoth said it provided the Cochrane research group that analysed Tamiflu with access to 3,200 pages of very detailed information, and says more information was made available on a password-protected site.
“Roche has made full clinical study data available to global health authorities, including the Therapeutic Goods Administration (TGA), for their review as part of the licensing process,” the statement says. ”It is the role of global health authorities to review detailed information on medicines when assessing benefit and risk.”
But Chris Del Mar says the TGA is not resourced to properly review the vast amount of information it is sent. He says the better-equipped US Food and Drug Administration (FDA) has rejected some claims made by Roche, including that Tamiflu reduces the complications of influenza and hospitalisations.
A spokeswoman for the TGA says the Australian Government stockpiled $179 million worth of Tamiflu and the related antiviral Relenza. She says TGA approves Tamiflu in Australia for the treatment and prevention of influenza but is yet to see the full data on the drug’s effect on influenza complications and transmission.
“The TGA expects full study reports containing study protocol, reporting analysis plan, statistical analysis plan and individual patient data to clarify outstanding issues. These full clinical study reports are at present unavailable to us.”
And those reports in the TGA’s possession so far are being kept secret.
“At the current time the TGA does not make full clinical study reports publicly available as they are provided to the TGA as commercial-in-confidence information at the time of an application,” the TGA spokeswoman said.
The TGA is currently developing a policy on the disclosure of commercially confidential information.
Meanwhile, European regulators agree financial conflicts of interest can distort research findings and that clinical trial data should not be kept secret.
But they challenge the idea that independent academics are free from conflicts of interest.
“Personal advancement in academia, confirmation of previously defended positions, or simply raising one’s own visibility within the scientific community may be powerful motivators,” write representatives from a number of European regulators in a response to Professor Del Mar, appearing in the same issue of PLoS Medicine.
“More often than not, ego trumps money.”
Chris Del Mar disagrees, saying while professional conflicts of interest exist, “a few crackpot academics at a few tin-pot universities” would be no match for the huge financial interests of big pharmaceutical companies.
A group of regulators led by the European Medicine Agency’s Senior Medical Officer, Hans-Georg Eichler, have published a responding point of view – in PLoS – essentially agreeing with Del Mar’s group.
First and foremost, we agree that clinical trial data should not be considered commercial confidential information; most patients enrolling in clinical trials do so with an assumption of contributing to medical knowledge, and “non-disclosure of complete trial results undermines the philanthropy” .
The potential benefits for public health of independent (re-)analysis of data are not disputed and, in an open society, trial sponsors and regulators do not have a monopoly on analyzing and assessing drug trial results. Yet, the different responsibilities of regulators and independent analysts have to be acknowledged. Regulators, unlike academicians, are legally obliged to take timely decisions on the availability of drugs for patients, even under conditions of uncertainty.
Going beyond the merits of independent meta-analysis, we foresee other, potentially more important benefits from public disclosure of raw trial data. For example, RCT datasets enabled the development of predictive models for patient selection to appropriate treatments. Taking this notion a step further, we envisage machine learning systems that will allow clinicians to match a patient’s electronic health record directly to RCT and observational study data sets for better, individualized therapeutic decisions.
Large, information-rich datasets are needed to support the computer science and artificial intelligence research required to develop and test these applications. Developing such tools is usually not a priority for, and often beyond the capabilities and resources of, even the largest pharmaceutical companies. These endeavors might best thrive in an environment that invites research from beyond the current stakeholders in health. Making rich datasets available for research is a means to open health research.
The full article in response is available online at: www.plosmedicine.org/article/1001202
Doshi P, Jefferson T, Del Mar C (2012) The Imperative to Share Clinical Study Reports: Recommendations from the Tamiflu Experience. PLoS Med 9(4): e1001201. doi:10.1371/journal.pmed.1001201
April 10, 2012
Peter Doshi - Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
Tom Jefferson – The Cochrane Collaboration, Roma, Italy
Chris Del Mar - Centre for Research in Evidence-Based Practice, Bond University, Gold Coast, Australia
Hans-Georg Eichler - European Medicines Agency (EMA), London, United Kingdom
Eric Abadie - Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS) Saint-Denis, France
Alasdair Breckenridge - Medicines and Healthcare products Regulatory Agency (MHRA), London, United Kingdom
Hubert Leufkens - Medicines Evaluation Board (CBG-MEB), Den Haag, The Netherlands
Eichler H-G, Abadie E, Breckenridge A, Leufkens H, Rasi G (2012) Open Clinical Trial Data for All? A View from Regulators. PLoS Med 9(4): e1001202. doi:10.1371/journal.pmed.1001202
Published: April 10, 2012
source: research media