Several sources today reported on British Medical Journal articles that show that not all human trial clinical data is being reported. Apparently, this is shocking to many clinicians and the public -- but also reflects charges critics have made for years (without the needed proof).
The BMJ is one of a number of journals to take developers to task on their data reporting practices. But despite the new mandates, there's no evidence that the pharma industry is drawing any closer to achieving true transparency. The BMJ concludes that some developers are purposefully keeping some data under lock and key, or publishing it on obscure sites. They want an end to what they call a "culture of haphazard publication and incomplete data disclosure."
These articles confirm the fact that a large proportion of evidence from human trials is unreported, and much of what is reported is done so inadequately. The absence of the data about harm in trials can harm patients, and incomplete data about benefit can lead to wasted costs to health systems. Moreover, researchers or others who deliberately conceal trial results breach their ethical duty to trial participants.
In BMJ, one paper examined unpublished evidence of existing meta-analyses of nine drugs approved by the FDA in 2001 and 2002, but found identical estimates of drug efficacy in only three of 41 cases, or 7 percent. In the remaining cases, estimates of drug efficacy were evenly split between more (19/41) and less (19/41). Missing data did not always reduce estimates of drug benefits, as this study shows that “publication bias” can cut both ways. Each increment of data can change the overall picture, but in most cases with no certainty that the picture is complete.
Prior registration of all trials became a condition for later publication in 2005. Yet, a survey of NIH funded research in the United States between 2005 and 2008 shows that only 46 percent of studies were published in a peer reviewed biomedical journal indexed by Medline within 30 months of trial completion. And three years later, one third still remained unpublished. The law calls for publication of all Government sponsored trial data in 12 months. Apparently, that doesn't mean much in terms of behavior.
Meanwhile, another paper found that at least 3,000 records of randomized controlled trials entered into Medline between 2006 and 2011 were NOT indexed, which means that many trials will be missed when entering the commonly used research term - randomized clinical trial - into the database. As the authors noted, important evidence in searches - design and methods, baseline characteristics, long term follow-up, and secondary data analyses - can be missed
It's like playing Hide N Seek -- searching all over through documents in regulatory bodies and drug companies to piece data together that should have been freely available. Even when data on individual participants are made available, they only form part of the picture, and Ahmed and colleagues describe the problems of fitting in such data when the whole picture is not known.
Past failures to ensure proper regulation and registration of clinical trials, and a current culture of haphazard publication and incomplete data disclosure, make the proper analysis of the harms and benefits of common treatments almost impossible for systematic reviewers. Patients will have to live with the consequences of these failures for many years to come.
The main challenge is to ensure better systems for the future. This may require the global organisation of a suitable shared database for all raw data from human trials— perhaps the next job for the World Health Organization. Concealment of data should be regarded as a serious ethical breach, and clinical researchers who fail to disclose data should be subject to disciplinary action by professional organisations. This should serve as a wake-up call to both the NIH and the FDA to restrict grants to researchers who receive government funds, but violate the rules. This may achieve quicker results than legislation in individual countries, although this is also desirable.
See PharmaGossip, Pharmalot and Fierce Biotech reports.
Posted by Bruce Lehr Jan 4th 2012
