The death of a volunteer in a calamitous drug trial in France last week renewed concerns about the safety of early-stage human testing and the lack of a comprehensive public database that tracks the outcomes of such clinical trials.
The victims, including some hospitalized with possible brain damage, were taking part in a Phase 1 trial of an experimental drug intended as a possible painkiller or treatment for mood and anxiety disorders. Such trials are small-scale tests conducted on healthy volunteers to examine the safety of a drug — normally after promising laboratory and animal assessments. They are supposed to pose little risk of harm to the healthy volunteers.
But the results of Phase 1 trials are not required to be publicly released to data repositories in Europe or the United States. That keeps the public and researchers from knowing just how often serious adverse events occur in these trials. And if bad outcomes go unreported, scientists working with similar drugs could unknowingly proceed with potentially hazardous studies.
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“It’s too early to know what went wrong in France,” said Dr. Ben Goldacre, a fellow at the University of Oxford and cofounder of Alltrials.net, which advocates for disclosure of clinical research. “But it’s really important that we do everything we can to address the known risks around Phase 1 trials,” including greater public disclosure of the trials and their results.
STAT reported last month that most medical research institutions in the United States flagrantly violate a federal law requiring public reporting of results of later-stage clinical trials, which examine both the safety and effectiveness of experimental drugs. Phase 1 trials are exempt from those disclosure rules, though sponsors can voluntarily provide results.
A new STAT analysis of about 7,700 Phase 1 trials registered as of last September on ClinicalTrials.gov — a data repository operated by the National Institutes of Health — showed results had been reported for fewer than 1 in 10. Bial, the Portuguese pharmaceutical company that sponsored the French trial, voluntarily posted data for 22 of its 37 registered Phase 1 trials, a far higher rate than the average.
Among 541 Phase 1 studies registered in the European equivalent of ClinicalTrials.gov, none provided results for public view.
Some companies publish Phase 1 results on their websites or report the results in scientific journals, said Jennifer Miller, a New York University medical ethicist who studies clinical trial transparency and supports universal reporting.
Clinical trial reporting lapses visualized
STAT examined data reporting for all institutions – federal agencies, universities, hospitals, nonprofits, and corporations – required to report results to ClinicalTrials.gov for at least 20 human experiments since 2008. This visualization shows the first comparative analysis of their performance. Among the groups, just two companies provided trial results within the legal deadline more than half the time. Most – including the National Institutes of Health, which oversees the reporting system – violated the law the vast majority of the time.
Percentage of clinical trials by entity that have late or no results:
Deaths appear to be rare during Phase 1 trials, but serious and unexpected injuries do occur. A 2015 study in the journal BMJ looked at 394 Phase 1 trials involving a variety of drugs and biologic substances. It found 11 serious adverse events related to the experimental drugs or biologics. These included hospitalizations for flu-like symptoms and diarrhea, and vaginal bleeding that led to a hysterectomy.
The BMJ finding that one serious event occurs in every 36 studies, if it’s extrapolated to all Phase 1 trials, suggests that hundreds of notable problems go unreported to any central public repository, if they are reported at all.
The most recent Phase 1 trial known to have caused grievous harm occurred in London in 2006, involving an experimental arthritis drug, TGN1412. One of the six men tested suffered heart failure and the loss of his fingers and toes. The volunteers and their families were outraged to learn that a similar drug had been found potentially dangerous years earlier, but no results of the tests had been made public.
After the TGN1412 debacle, authorities in the United Kingdom called for greater transparency in Phase 1 trials.
“We already know that secrecy about results is an issue. So why have we failed to address this?” Goldacre said about Phase 1 trials in general. “It makes no sense.”
NIH has proposed a policy, which it hopes to implement this spring, to require Phase 1 results on studies it underwrites to be posted to ClinicalTrials.gov. But the US Food and Drug Administration has not followed suit on requiring reporting the results of corporate-funded studies.
An FDA spokesperson provided a written statement: “Given the recency of the tragic events in France and because we do not have all of the facts related to the conduct of the trial, the agency has not had the opportunity to consider the implications, if any, under FDA’s statutory and regulatory provisions.”
NIH had no immediate comment.
“If we want to have a big impact on trial and drug safety, as well as trust in the research enterprise, then we should require full transparency for both private and publicly funded trials,” NYU’s Miller said. “It doesn’t make a lot of sense to have varying disclosure requirements.”
UK authorities also suggested staggering the administration of new drugs over time, rather than providing them to all trial participants at once, as apparently occurred in the recent French trial. Goldacre called for an audit on how widely that basic safety factor has been adopted in the industry.
It remains unclear if there were transparency lapses with the experimental drug in the French case. When the alarming results of this month’s trial were immediately made public, STAT found no trial registrations or results reported for any studies of that drug, called BIA 10-2474, on either the European or US systems for recording clinical studies.
Trial sponsor Bial said in a statement that the trial had been approved by French regulators and that 108 other people had previously taken the drug without serious problems. Bial said it was cooperating with authorities.
The man who died has not been identified publicly. Five other men who took the drug remain hospitalized.
A private evaluation firm, Biotrial, based in Rennes, France, conducted the test for Bial. Biotrial has conducted numerous Phase 1 trials for drug firms of experimental drugs intended to treat Parkinson’s disease, hypertension, epilepsy, hepatitis C, and other ailments. In a statement, the company said it had followed proper procedures.