Wednesday, October 30, 2013

AllTrials contd. Unpublished Trial Data Violates An Ethical Obligation To Study Participants

29% of large clinical trials remain unpublished five years after completion and, of those, 78% have no results publicly available, according to a paper published yesterday.

This means that an estimated 250,000 people have been exposed to the risks of trial participation without the societal benefits that accompany the dissemination of their results, worry the authors. Of course, the participants all volunteered for the trials and had informed consent and many were even paid so claiming they were 'exposed to the risks' is emotional verbage designed to guide the public into one conclusion: all trial results should be published.

Of course, reality is not so simple. The public is already barraged with an array of media claims about studies that are not even published (Oreos are as addictive as cocaine,anyone?) - adding numerous trials with null results doesn't help. And if the trials were not funded with taxpayer money - most drug trials are not - there is no reason failures of products that will never get to market need to be made available, unlike government-controlled science that should obviously be published because the public paid for it.

Yet they argue that non-publication "violates an ethical obligation that investigators have towards study participants" and call for additional safeguards "to ensure timely public dissemination of trial data" because, they argue, randomized clinical trials are not just designed to show a product works but are a critical means of advancing medical knowledge - an argument that is not part of any law or regulation. 

Regardless, the authors on BMJ say trials depend on the "willingness of people to expose themselves to risks" and that they do so because society will eventually benefit from the knowledge gained from the trial, not because they are paid or may get a benefit from an experiment treatment. Clearly, the problem is not unpublished trial data, it is instead terrible informed consent policies. 

But when trial data remain unpublished, the societal benefit that may have motivated someone to enroll in a study remains unrealized. Who are these altruistic people undergoing experimentation with untested drugs for the common good? Best of luck finding them. Few results of that kind get published historically because journals are uninterested in publishing the results of negative trials.

US law requires that trials involving human participants now be registered - and their results posted - on the largest clinical trial website But the authors believe that this legislation has been largely ignored, yes companies are just brazenly violating federal law, it os contended, and they set out to estimate the frequency of non-publication of trial results and, among unpublished studies, the frequency with which results are unavailable in database.

They searched PubMed, Google Scholar, and Embase and identified 585 trials with at least 500 participants that were registered with and completed prior to January 2009 - before the mandatory requirement that came into effect September of 2009. The average time between study completion and the final literature search (November 2012) was 60 months for unpublished trials. Registry entries for unpublished trials were then reviewed to determine whether results for these studies were available in the results database.

Of 585 registered trials, 171 (29%) remained unpublished. Of these, 133 (78%) had no results available in Non-publication was more common among trials that received industry funding (32%) than those that did not (18%). Fair enough, except picking trials 8 months before the requirement skews the results and they used P values of <0.05 as statistically significant, which is fine, but the 0.05 threshold is arbitrary - it just happens to be common in reviews because P values are determined by comparing the test statistic against tabulations of specific percentage points of statistical distributions. 

There are also other reasons trials were exempt, which the authors leave out of their discussion - the studies may be exempt, they may not be completed or the date for submission may not have passed.

Accountability is fine but drug discovery is expensive, time-consuming and prone to overwhelming levels of failure. Demonizing drug companies will leave the public with nothing but academia or government to create new products - as the National Health Service's $9 billion IT and America's fiascoes have shown, when government can't even make websites work, they certainly can't be relied on to advance medicine.

In the same issue, BMJ engages in scaremongering about swaddling infants and dismisses concern that overcaffeinated energy drinks might be a health concern for developing children. Their poll question for the week is "Can New York City continue to be a global leader in public health under a new mayor?" when the evidence has shown that health has declined under the current mayor. Use caution when reading advocacy masked as data.

Citation: Christopher W Jones, Lara Handler, Karen E Crowell, Lukas G Keil, Mark A Weaver, Timothy F Platts-Mills, 'Non-publication of large randomized clinical trials: cross sectional analysis', BMJ
29 October 2013
 347 doi: 10.1136/bmj.f6104

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