How Important Is It To Report Negative Data from Clinical Trials?
The premise that negative results should be treated by omission gave rise to a number of ethical challenges from major sources in recent decades.
Poor Compliance With Regulations
These broad interpretations all conspired to create large gaps in the way requirements were viewed. A 2014 meta-analysis by Saito and Gill7 of 400 clinical trials randomly selected from the clinicaltrials.gov database found that 29% (n=118) failed to publicly report results within 4 years of completion of the trial. The mean number of days to publication among the remaining 282 studies was 647, still far in excess of the 1-year requirement.7 Saito and Gill noted that many of the studies were smaller and were industry funded. “This constitutes reporting bias and threatens the validity of the clinical research literature in the US,” they concluded.
The World Medical Association Declaration of Helisinki Ethical Principles for Medical Research Involving Human Subjects, updated in 2008,8 required that all studies involving human participants be publicly registered to a “free access” website before the first patient is enrolled. The declaration charged authors, editors, and publishers of medical research with the ethical obligations of providing comprehensive and timely reporting of all study results.8
“Unfortunately, despite these important steps, nonpublication is still an enormous problem,” Dr Jones said. “Regulations and policies aimed at addressing nonpublication have been unsuccessful in the past, likely because enforcement is challenging and there is significant variability among investigators with respect to understanding their obligations toward making data available.”
Financial pressure is a main factor, as both the Saito and Gill and Jones et al studies found large percentages of unreported trials had industry support. Research conducted by Danielle Fanelli at the University of Edinburgh revealed that competition for funding and positions often drove researchers to drop lines of investigation that did not yield significant results in favor of trials that had better chances of success and publication.9,10
“I think that until very recently neither the medical community nor the public have recognized the magnitude of the nonpublication problem and the profound impact it can have on medical decision-making. I hope that this is starting to change and that both physicians and patients will demand that investigators and study sponsors do better,” Dr Jones challenged.
- WHO Statement on Public Disclosure of Clinical Trial Results [press release]. Washington DC: World Health Organization. http://www.who.int/ictrp/results/reporting/en/. Published April 9, 2015. Accessed March 8, 2017.
- Jones CW, Handler L, Crowell KE, et al. Non-publication of large randomized clinical trials: cross sectional analysis [published online October 29, 2013]. BMJ. doi: 10.1136/bmj.f6104
- Hudson KL, Lauer MS, Collins FS. Toward a new era of trust and transparency in clinical trials [published online October 4, 2016]. JAMA. doi: 10.1001/jama.2016.14668
- Food and Drug Administration Modernization Act (FDAMA) of 1997 [press release]. Silver Spring, Maryland: Food and Drug Administration. https://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDAMA/default.htm. Published November 21, 1997. Accessed March 9, 2017.
- Gopal RK, Yamashita TE, Prochazka AV. Research without results: inadequate public reporting of clinical trial results. Contemp Clin Trials. 2012;33:486-491.
- Zarin DA, Tse T. Moving toward transparency of clinical trials [published online March 7, 2008]. Science. doi: 10.1126/science.1153632
- Saito H, Gill CJ. How frequently do the results from completed US clinical trials enter the public domain?—a statistical analysis of the ClinicalTrials.gov database [published online July 15, 2014]. PLoS ONE. doi: 10.1371/journal.pone.0101826
- 8. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects [press release]. Seoul, South Korea: World Medical Association. http://www.wma.net/en/30publications/10policies/b3/17c.pdf. Published October 2008. Accessed March 9, 2017.
- Fanelli D. Do pressures to publish increase scientists' bias? An empirical support from US States Data. [published online April 21, 2010]. PLoS ONE. doi: 10.1371/journal.pone.0010271
- Fanelli D. Negative results are disappearing from most disciplines and countries [published online September 11, 2011]. Scientometrics. doi: 10.1007/s11192-011-0494-7