Underreporting Negative Clinical Trial Data Raises Ethical Concerns With WHO, FDA, NIH
A number of organizations recently raised ethical concerns linked to researchers not reporting negative results of clinical trials.
In an environment where pharmaceutical research is expanding far into theoretical territory with genetic studies and patient-targeted therapies with narrow applications, the drive for early success continues to exert heavy pressure on the reporting of clinical trials. Increasingly, the scientific community is coming to realize the invaluable role that negative outcomes play in the understanding of medicine as a whole.
Early in clinical trial research, the choice to publish was initially left in the hands of the researchers and the publishing community who determined what was and was not newsworthy. As a result, trials with negative results were often abandoned without publication of the data collected, often on the presumption that it represented wasted time and resources. Negative data were often viewed as inconsequential and, therefore, “null.”
Health Organizations Raise Questions About Clinical Trial Data
The premise that negative results should be treated by omission gave rise to a number of ethical challenges from major sources in recent decades — including the World Health Organization (WHO), the National Institutes of Health (NIH), and the U.S. Food and Drug Administration (FDA) — to restructure clinical trial reporting to include all relevant data from all clinical trials performed.
Several objections were specifically raised to the practice of not reporting negative clinical trial results, citing that it:
- causes duplication of negative results from other investigations;
- puts new trial patients at unnecessary risk;
- distorts the evidence base; produces incomplete knowledge and creates misconceptions that get incorporated into guidelines and daily practice;
- undermines trust of patients participating in trials if the results are never published; and
- results in poor allocation of product development resources and slows drug development.
From a scientific standpoint, the main objection to nonreporting of negative results was that it contributes to a body of knowledge that was at best, incomplete, and at worst, wrong.
According to a statement by the WHO, “Researchers have a duty to make publicly available the results of their research... Negative and inconclusive as well as positive results must be published or otherwise made publicly available.”1
A cross-sectional analysis of published literature by Christopher Jones, MD, from the Cooper Medical School of Rowan University, Camden, New Jersey, and colleagues showed that the results of nearly one-third of all large-scale clinical trials with more than 500 participants registered before 2009 were never published.2 The authors reported that data collected from an estimated 299,763 participants enrolled in 171 of 585 trials (29%) conducted from November 1999 to January 2009 had not been published up to 60 months after the close of the trial.2
Additionally, results from the majority (78%, 133/171) were not reported on Clinicaltrials.gov.2 Results from nearly twice as many studies that were industry funded were not published (32%, 150/468) compared with those funded by other sources (18%, 21/117).
“We looked at very large trials completed by 2009 and found that nearly 30% remained unpublished by 2012,” Dr Christopher Jones told Rheumatology Advisor. “Since then, there has been progress on the regulatory front with respect to trial transparency and data availability. It was very encouraging to see the WHO's recent statement,1 as well as the policy released by the NIH last year,3 both of which sent clear, emphatic messages reinforcing the importance of making trial results public.”
Path Toward Balanced Reporting and Transparency
In 1997, the United States Congress passed the Food and Drug Modernization Act to establish the current NIH online registry, clinicaltrials.gov (operated by the National Library of Medicine), designed to register clinical trials of drugs, biological products, and medical devices. Authors were required to register their trials within 21 days of recruitment of the first participant, although reporting of ultimate results was not required.
In 2005, the WHO Assembly led support to this effort with the release of a resolution requiring “unambiguous identification of all interventional clinical trials,” and by the creation of the International Clinical Trials Registry Platform, stating that: “The registration of all interventional trials is a scientific, ethical and moral responsibility.”1
The subsequent Food and Drug Administration Amendments Act (FDAAA) of 2007 required basic study results to be posted to clinicaltrials.gov within 1 year of completion of the study. 4 The FDAAA requirements were written for “applicable clinical trials,” which did not specifically reflect phase 1 preclinical studies and most trials prior to application with the FDA.5,6