Without full access to all available data, both published and unpublished, the current process for conducting systematic reviews of clinical trial evidence “is not sufficiently rigorous, and in some cases it risks turning into unsolicited authoritative advertising for the drug industry”, claim researchers from the Cochrane Acute Respiratory Infections Group.
In other words, “we need access to all unpublished data, even of trials published in the peer reviewed literature”, says the international team led by Tom Jefferson from the Cochrane Collaboration’s Acute Respiratory Infections Group in Rome, Italy in an article for the BMJ.
“It is time the media, the Cochrane Collaboration, and any reader interested in knowing what they are prescribing or are being prescribed increase the pressure on policy makers,” Jefferson et al comment. “If you swallow a medication, you need to know how it works – for real.”
The Cochrane researchers base their arguments on the already contentious issue – highlighted in an updated systematic review of the efficacy and safety of Roche’s antiviral oseltamivir (Tamiflu) that was published in the BMJ in December 2009 – of whether the publicly available data on oseltamivir are sufficient to draw any conclusions abut the drug’s ability to reduce the risk of complications such as pneumonia in otherwise healthy adults with influenza.
On that occasion, Roche issued a detailed rebuttal of the Cochrane researchers’ conclusions in a letter to the BMJ. This included claims that when the oseltamivir trials in question were conducted, it was not standard practice for study protocols or reports to be made public; and that Roche had sought to provide the full study data to Jefferson under a standard confidentiality agreement, which he had refused to sign.
The company also questioned at the time why the request for additional data on oseltamivir came from a Channel 4 television news team, rather than directly from the Cochrane researchers themselves, something that cast doubt on “whether the motives for inquiries were truly for clarity and scientific validation”.
The latest BMJ article revisits this debate, including the decision to exclude from the 2009 review findings from unpublished trial data incorporated into a manufacturer-funded meta-analysis (led by Laurent Kaiser) of 10 clinical trials with oseltamivir, only two of which had appeared in the peer-reviewed literature.
Subsequently, Jefferson et al note, “and perhaps in response to the enormous publicity generated by the joint BMJ-Channel 4 News investigation of oseltamivir”, Roche pledged publicly to make available the full clinical study reports on the drug.Still lacking data
“We expected that these reports would provide sufficient detail to verify the findings of the Kaiser meta-analysis,” they add.
“However, what Roche provided was not the full study reports of the 10 trials but module 1 of seven trial reports. The tables of contents showed that the full reports probably comprise four or five modules. Unfortunately, module 1 does not include the analysis plan, randomisation schedule details, the study protocol with a list of deviations, or detailed case histories for patients experiencing adverse events.”
The additional data provided, while incomplete, are another reason for questioning the integrity of the published evidence, the Cochrane researchers contend.
“For example, the first of the two published studies in the Kaiser meta-analysis does not mention serious adverse events, and the second states that ‘there were no drug-related serious adverse events’. However, the partial study reports that Roche made available to us list 10 serious adverse events (in nine subjects) in the two trials, three of which were classified as possibly related to oseltamivir.”
Make it freely available
The answer to concerns raised by the oseltamivir data and other meta-analyses that have combined published and unpublished data “is to make the data freely available: we should accept nothing less than a full dataset,” the Cochrane group argues.
“Before licensing a drug—and certainly before large purchase decisions are made—our governments and policy makers should ensure that all researchers can access data in sufficient detail to allow for the independent exploration and re-analysis of trials.”
Researchers, the public, and the lay and scientific media “will need to work together to put pressure on industry to embrace the ethical responsibility to release data in the public interest”, Jefferson et al suggest – something that can only be achieved at present through legal action (as in the case of GlaxoSmithKline’s diabetes drug Avandia (rosiglitazone), they say.
“Ideally, regulators would make full clinical study reports publicly available once a regulatory decision is reached,” the Cochrane group proposes, while acknowledging this is “a daunting task considering that the FDA submission for oseltamivir was at least 363 volumes”.
For the moment, Jefferson et al continue, “we call on journals to require, as a condition for consideration of publication of a randomised trial, submission of the most detailed report available (anonymised to protect patient privacy), in addition to the summary manuscript for publication … If patient privacy can be assured, posting the detailed report as an online supplement will also improve post-publication review”.An overview of the trial programme should also be submitted, explaining the rationale and findings of each trial, the researchers add, commenting: “We need to understand how and why a particular trial was designed and conducted – that is, how every trial can potentially advance our knowledge”.
Anyone conducting experiments on humans “has obligations transcending patents and commercial confidentiality”, the Cochrane group observes. “We must remember that trial participants are performing a service to humanity, entering a potentially risky situation for the sake of determining the toxicity and effectiveness of a new drug. Withholding the results of such trials, and in some cases archiving them in such a way that they come to light only after prolonged and detailed investigation, seems ethically dubious”.
Last year a joint investigation by the BMJ and the Bureau of Investigative Journalism took another potshot at Roche in relation to global plans for coping with a flu pandemic. The investigation found that the World Health Organization’s 2004 guidance on the use of antivirals in a pandemic was prepared by an influenza expert who had received payment from Roche and from GlaxoSmithKline, which markets Relenza (zanamivir), for lecturing and consultancy work.