A study published in JAMA Internal Medicine in February found that serious violations of good clinical practice discovered by the Food and Drug Administration (FDA) at clinical trial sites are not mentioned in peer-reviewed publications in which the trial results are published.
Author Charles Seife, MS, professor at the Arthur L. Carter Institute of Journalism at New York University, and graduate student assistants searched an FDA database of inspection results to find investigators and clinical trial sites that received “official action indicated” (OAI), the most severe classification. The researchers put in a Freedom of Information Act (FOIA) request for details on the inspections, and received heavily redacted documents of 20 related investigations. They also searched the FDA database and used official notifications of regulatory actions against investigators.1
“This investigation has found numerous studies for which the FDA determined there was significant evidence of fraudulent or otherwise problematic data. Such issues raise questions about the integrity of a clinical trial, and mention of these problems is missing from the relevant peer-reviewed literature,” Seife wrote.1
“No corrections, retractions”
In all, Seife and researchers found 57 published clinical trials between 1998 and 2013 that found evidence of one or more problems, including: “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%),” according to the study.1
Of the 78 publications from the trials in which FDA violations were found, only three mentioned the violations. “No corrections, retractions, expressions of concern, or other comments acknowledging the key issues identified by the inspection were subsequently published,” Seife wrote.1
Seife gave examples of unreported violations, including the following:
• In a clinical trial of anticoagulant drug rivaroxaban, eight of 16 site inspections received OAI for infractions such as falsification, unauthorized unblinding, and “concerns regarding improprieties in randomization.” The FDA deemed the entire study unreliable — a determination that was not mentioned in articles related to the study results or trial.1
• Clinical trial records for a chemotherapy study were falsified by a researcher, partly because already-falsified patient records led to the death of a research subject with impaired kidney and liver function. The subject’s condition was hidden, and the subject died after the first dose was administered. The researcher was sentenced to prison after pleading guilty to criminally negligent homicide and fraud. The same researcher also falsified records in other studies. The falsifications and patient death were not reported in subsequent journal articles on the studies.1
• A patient had a foot amputated two weeks after receiving stem cell treatment in a trial involving patients with ischemic limbs. Despite this, the article on the study stated that “all patients recognized and were aware of major clinical improvements in the treated (more ischemic) leg, despite no significant clinical changes in the control (less ischemic) leg.”1
The FDA does not notify peer-reviewed journals about an OAI determination for a clinical trial that the journals may have published, nor does the agency inform the public, Seife noted. FDA site inspection documents received through the FOIA request were heavily redacted, making it impossible to match many of the documents to published clinical trial information. “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,” Seife stated. “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.”1
Implications for research
The implications can be felt in the research community and the public, according to Seife. “For the research community, it means that you cannot trust that findings of research misconduct are reflected in the peer-reviewed literature — that in the majority of cases, even when the FDA has documentation of fraud, there is no indication in the peer-reviewed literature that this has gone on at all,” Seife said in an audio interview with JAMA Internal Medicine. “For the public, you have to be aware that the FDA is finding problems but isn’t always telling the public about it. So you have to be aware that the peer-reviewed literature is not fully reflective of the problems that are found with the scientific trials.” (The interview can be found at http://archinte.jamanetwork.com/article.aspx?articleid=2109855.)
One possible remedy, Seife noted in the study, is that the FDA could make unredacted information on clinical trial site misconduct available to the public and to the scientific community, either through ClinicalTrials.gov or through a separate database. “[H]owever, 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,” Seife wrote. “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.”
- Seife C. Research Misconduct Identified by the US Food and Drug Administration: Out of Sight, Out of Mind, Out of the Peer-Reviewed Literature. JAMA Intern Med. Published online February 09, 2015. doi:10.1001/jamainternmed.2014.7774.