Two stories in the March/April 2016 issue of Research Practitioner recently have been updated. The first, “Bial Trial Highlights Reporting Deficiencies,” highlighted a study by the publication STAT that looked at the mandatory reporting of results of human studies of new treatments to the federal government's ClinicalTrials.gov database.1
In the study, STAT identified about 9,000 trials in ClinicalTrials.gov subject to the law’s disclosure requirements. The analysis looked at the 98 universities, nonprofits, and corporations that served as sponsors or collaborators on at least 20 such trials between 2008 and Sept. 10, 2015. Only drug companies Eli Lilly and AbbVie complied with reporting requirements more than half the time, STAT says. Results from academic institutions arrived “late or not at all 90% of the time, compared with 74% for industry.” In addition, STAT looked at data from ClinicalTrials.gov for reporting of NIH research. The data show that NIH scientists’ reporting of results within the legal deadline peaked at 38% in 2013. “Counting results reported late, NIH staff performance reached 90% for studies due in 2012 but has dropped since then,” the report says.
Overall, research results were disclosed late or not at all at least 95% of the time since reporting became mandatory in 2008, according to STAT. Although pharmaceutical companies have been criticized for their lack of transparency, “major medical schools, teaching hospitals, and nonprofit groups did worse overall — many of them far worse,” says the author of the report.
Vice President Joe Biden saw the STAT report and was not happy. Speaking at a cancer summit at Howard University in Washington, DC, on June 29, Biden said, "Doc, I'm going to find out if it's true," he said. "And if it's true, I'm gong to cut funding. That's a promise."2
Francis S. Collins, director of the NIH, said at the summit that NIH has the authority to pull funding for individual investigators and entire organizations if they are found to not be in compliance of research guidelines. “There is going to be a lot of clout here,” he said, as reported by The News Journal.3
Institutions can be fined for nonreporting or have clinical research suspended, but the government has not levied a single fine, STAT says. Collins said the administration is close to issuing a final rule with “teeth,” according to the Washington Post.1 “This issue is going to be solved.”
Possible criminal charges over trial death
The second article, “Trial volunteer death throws spotlight on disclosure,” told the story of French trial that was studying an experimental fatty acid amide hydrolase (FAAH) inhibitor developed by Bial, a Portuguese pharmaceutical company. In January, a healthy volunteer in the study died from neurological symptoms and five others were hospitalized. On June 14, French prosecutors announced that they were opening an involuntary manslaughter investigation to determine whether there was a criminal element in any mistakes made or whether it was simply the result of clinical risks involved.4
Biotrial, the contract research organization (CRO) that conducted the Phase 1 trial in Rennes, France, tells in-Pharmatechnologist.com that it is not surprised by the investigation. “This is a normal decision, which was expected as part of a complex investigation that requires expertise and investigations abroad. As we have done since the first day of the administrative and judicial investigations, we will continue to cooperate in the utmost transparency with investigators,” the Biotrial statement says. “The judicial investigation guarantees respect for the adversarial principle and the rights of people, which are highly valued. We are convinced that justice alone will make the truth about this dramatic accident, truth which is owed to the victims and their families, but also to all the Biotrial staff.”5
Bial issued a statement on May 23 reiterating that it made proper decisions on the compounds’ escalating doses. “Towards the report conclusion regarding the escalating doses, including the passage from 20 mg to 50 mg, BIAL notes that the safety and tolerability profile of BIA 10-2474 was favorable up to 20 mg. There were no alerts, or signals in any of the safety parameters collected from any of the previous cohorts that could have anticipated the tragic accident. The integrated analysis of single (up to 100 mg) and multiple doses of drug exposure did not reveal any unexpected behavior of the molecule. Therefore, given the data collected in the previous phases of the trial, there was no reason to modify the escalation of doses forecasted and approved by the authorities in the trial protocol.”6
Bial says its “key priority” is to accurately and exhaustively understand what happened in the clinical trial. However, Bial says that investigators have not given the company access to the complete medical data of the volunteers. This includes the autopsy data of the volunteer who died, which Bial says is an “essential element to pursuit a full investigation on the accident.”6 Bial also wants to know the procedures carried out by the Rennes University Hospital, which cared for the volunteers after the adverse event.
Back in January, a physician argued that a manslaughter investigation would be a “devastating blow to research and development as any drug manufacturer has to now worry about criminal charges in the rare instance that a subject dies or is permanently disabled.”7 “The Phase I trial is one of the most important steps in getting a new drug or medical device approved; these early clinical tests are designed to test different doses for toxicity and tolerance, and follow animal testing,” says Lila Abassi, a physician at SUNY (State University of New York) Downstate Medical Center.
“Seeing as how the entire process had followed all safety protocols, not only is it ludicrous to charge anyone with manslaughter but entirely unfounded,” she concludes. “With the prescription pain killer abuse epidemic being what it is, any attempt at discovering new drugs is welcome. Drug approval is a process and the results may not be what we would hope for but before we send out a lynch mob, it’s important to reflect on where we would be if we criminalized the process.”7
By Sue Coons, MA
This article was reprinted from Research Practitioner, Volume 17, Number 4, July-August 2016.