Carl Heneghan, Director of the University of Oxford’s Centre of Evidence-Based Medicine, discusses recent developments in access to clinical-trial data.
The Pharmaceutical industry and drug regulators treat clinical data, submitted at the time of regulation, as confidential documents. At the same time, and to make matters worse, medical journals have “evolved into information laundering operations for the pharmaceutical industry.” This situation is dangerous for the public health and inhibits the advancement of medical science.
In April 2012, Hans-Georg Eichler and colleagues published the view of European medicine regulators that, “clinical trial data should not be considered commercial confidential information.” Instead, clinical trials data including the raw data should be available for independent third party scrutiny. This is a bold step and means the European Medicines Agency is committed to proactive publication of such clinical data.
Why does access to clinical trial data matter?
The lack of access to clinical data has harmed patients, led to additional cost, and is preventing progress in many therapeutic areas. Rofecoxib, a non-steroidal anti-inflammatory drug, marketed by Merck & Co. is a prime example. Research published in JAMA demonstrated that two pivotal publications of industry-sponsored clinical trials of rofecoxib for Alzheimer’s disease did not include analyses of mortality, enabling the studies to conclude rofecoxib is “well tolerated.” In direct contrast, and at the same time as publication, Merck’s internal intention-to-treat analyses from the same trials identified a significant increase in total mortality. What is striking about this case is these mortality analyses were neither provided to regulators nor made public.
The story of oseltamivir (Tamiflu), an antiviral drug that is prescribed for the treatment of influenza and marketed by Roche, highlights the difficulties faced in accessing clinical trial data. Researchers who are attempting to review the effectiveness of oseltamivir (including me) are still waiting for access to clinical trial data three years after the first promise by Roche to make the data available. As far back as 2009, the US has stockpiled nearly US$1.5 billion dollars of oseltamivir. But, eight of the 10 trials on which effectiveness claims in adults were based have never been published. It was only in response to substantial publicity generated by a joint BMJ-Channel 4 News investigation that Roche publicly pledge to make its unpublished full clinical study reports available.
At the time, James Smith on behalf of Roche, published a point-by-point response in the BMJ stating, “as you will note from the replies below, Roche is, nevertheless, very happy to have its data reviewed by appropriate authorities or individuals, and has never concealed (or had the intention to conceal) any pertinent data.
Yet three years later, the data has still not been fully released. Fiona Godlee, editor of the BMJ, recently wrote, “Despite a public promise to release internal company reports for each Tamiflu trial … Roche has stonewalled.” In the last few weeks, Daniel O’Day of Roche stopped short of matching a promise from rival GlaxoSmithKline to make patient-level data from all company-sponsored clinical trials available on a routine basis. Roche said it had not handed over the full collection of data requested by researchers from the Cochrane Collaboration because the group refused to sign a confidentiality agreement.
A further recent example illustrates why access to data is so important. By accessing individual trial data, it was shown that aspirin reduces the likelihood that cancers will spread to distant organs by ~40%. Peter Rothwell, the lead author of the research, reported that one of the pivotal issues that allowed the mining of so much new information from these previous studies was “the paper records of trials, such as these aspirin trials, are archived for many years after the trials are completed and published. This means that if new questions arise later, as is often the case, the potential to look back at what happened is not lost.”
What does the EMA’s stance on clinical trial data mean for researchers?
At a recent workshop on clinical trial data and transparency, held at the EMA’s headquarters in London the Agency announced it is committed to proactive publication of clinical-trial data, once the marketing-authorisation process has ended. “We are not here to decide if we publish clinical-trial data, but how,” said Guido Rasi, executive director of the EMA. The EMA’s stance to open its doors to systematic scrutiny is a sizeable step towards the end of data secrecy.
The key for all research is reproducibility and data needs be made available for verifying published results and in some cases, such as the aspirin example, for conducting new or alternative analyses. The proactive publication of clinical trial data, by the EMA is expected to come into force by January 2014.
Dr Carl Heneghan is a Reader in Evidence-Based Medicine, Director of the Centre of Evidence-Based Medicine (www.cebm.net) and a General Practitioner (email@example.com)