Friday, 10 April 2015

This is Huge: Serious Research Misconduct in Almost 3/4 of FDA Inspected Clinical Trials – Hidden by Both Inspecting Agency and Researchers

First I had problems taking it in: Almost 75% of US clinical trials inspected over a period of 15 years by the Food and Drug Agency, responsible for upholding regulation in this area, display serious misconduct of various kinds. It can't be that bad, I asked myself; if it was, I would have heard something about it before – research ethics in medicine being one of my areas of expertise! Except that I wouldn't, since neither the FDA nor the researchers in question have reported these stunning findings to the outside world. That is, until Charles Seife, an MD but also a journalist, decided to have a look at FDA documents of some of the made inspections between 1998 and 2013. What he found is reported in a recent article in the journal JAMA Internal Medicine, where out of originally 600 trials, 101 where identified where the FDA had found strong reason of issuing complaint, and among these:

Fifty-seven published clinical trials were identified for which an FDA inspection of a trial site had found significant evidence of 1 or more of the following problems: falsification or submission of false information, 22 trials (39%); problems with adverse events reporting, 14 trials (25%); protocol violations, 42 trials (74%); inadequate or inaccurate recordkeeping, 35 trials (61%); failure to protect the safety of patients and/or issues with oversight or informed consent, 30 trials (53%); and violations not otherwise categorized, 20 trials (35%). Only 3 of the 78 publications (4%) that resulted from trials in which the FDA found significant violations mentioned the objectionable conditions or practices found during the inspection. No corrections, retractions, expressions of concern, or other comments acknowledging the key issues identified by the inspection were subsequently published.
 Seife concludes:

The FDA has legal as well as ethical responsibilities regarding the scientific misconduct it finds during its inspections. When the agency withholds the identity of a clinical trial affected by scientific misconduct, it does so because it considers the identity to be confidential commercial information, which it feels bound to protect. However, failing to notify the medical or scientific communities about allegations of serious research misconduct in clinical trials is incompatible with the FDA’s mission to protect the public health /... /
To better serve the public health, the FDA should make unredacted information about its findings of research misconduct more readily available. The agency should make sure that any substantial evidence of misconduct is available to editors and readers of the scientific literature /.../
... most of the burden for ensuring the integrity of the research in the peer-reviewed literature falls to the authors of the articles submitted to peer-reviewed journals. Currently, there is no formal requirement for authors seeking to publish clinical trial data to disclose any adverse findings noted during FDA inspections. Journals should require that any such findings be disclosed.
The nail on the head if there ever was one, and Seife is backed by an editorial, signed by three strong voices from the Yale and UCSF medical schools. FDA is liable to serious criticism for not proactively informing the scientific and medical communities, as well as the general public, of these matters. Journals which not immediately effect the standard indicated by Seife would deserve equally serious criticism. But the worst of all is the fact that such journal policies would be needed in the first place. 

The by far heaviest burden of criticism befalls those researchers, many of which have not only committed scientific fraud and serious ethical breaches, but have all in addition consciously choosen to actively surpress highly relevant information about the quality of the studies they have conducted. Not only is this relevant for the publication screening at journals to safeguard the quality of scientific publications. It is even more relevant for the assessment of the results reported in publications for the purpose of, e.g., licencing or decisions on clinical use, or public funding. These researchers have sold their scientific credibility and honour to whatever bidder (in the vast majority of cases, one suspects the pharmaceutical company funding the study) have incited them to keep mum. People doing such things have no place in either the academic or the medical community.

Seife has a popular report of the significance of his study in Slate, here.

This is, as far as I can see, a major research ethics and regulatory scandal, and it might just be hiding an even larger one. For, given the frequency of serious misconduct now revealed, one may very well ask what would be found if FDA was to cast its inspection net wider and inspect even more trials. And what would be the outcome of similar procedures in, e.g., Europe or Asia?