Now is the time for transparency and access to clinical-trial data
Director of the University of Oxford’s Centre of Evidence-Based Medicine, discusses recent developments in access to clinical-trial data.
PLoS: Speaking of Medicine
By Dr Carl Heneghan
December 7, 2012
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.
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.”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.
Roche may release full Tamiflu data as transparency debate rages
by Kevin Grogan
November 23, 2012
In the wake of intensive pressure concerning its stance on transparency, Roche has offered to discuss the possibility of finally publishing the complete raw dataset on its antiviral Tamiflu. As the European Medicines Agency held a workshop in London on access to clinical-trial data and transparency, the Swiss major revealed plans to set up "a multi-party advisory board comprising experts from academia and private institutions" to review the totality of Tamiflu [oseltamivir] data. It has invited the Cochrane Collaboration, which has repeatedly claimed that Roche has refused to provide full access to all its data which leaves questions about how well the drug works unresolved…Ben Goldacre, author of Bad Pharma, the publication of which has caused a stir among the sector for its criticisms of companies and regulators alike over their lack of transparency, said on Twitter that Roche had acted "in desperation". Dr Goldacre, who participated at the EMA workshop, added "not enough. Release the files". Meantime, the UK Government has announced that it will investigate pharma’s withholding of clinical trial data within the next 12 months [MPs to investigate pharma over witholding data, Sue Roche over Tamiflu data, says Cochrane, BMJ ups the ante on trial data transparency].
As a youth, I believed in beginnings and endings, I thought the firing on Fort Sumter started the Civil War and Appomattox ended it; that the Archduke Ferdinand’s Assassination began WW I and it ended with the Treaty of Versailles. It was our Civil Rights struggle in the South that helped me see that’s not how things work at all. Some people thought the DSM-III was the ending of the psychoanalytic captivity of psychiatry. I thought it was the beginning of a simplification of human experience. Neither of those things was right nor wrong. These great landmarks are just the moments when the forces of historical change reach a critical level and something has to happen, the transition from ending to beginning as my favorite and oft-quoted poet says:
In my beginning is my end. In succession
What we call the beginning is often the end
An easy commerce of the old and the new,