ARTICLE IN BRIEF
A trial testing the safety of an experimental agent in healthy volunteers resulted in a death and neurologic impairments. Bioethicists discuss what may have gone wrong with the trial and what principles should apply to safe and ethical research conduct.
A phase 1 drug trial in France that left one healthy volunteer dead and three others with neurologic impairments has focused attention on how to build more safeguards into drug testing and better promote the sharing of early testing results with the scientific community.
The drug trial gone awry is the focus of a November 3 report in The New England Journal of Medicine (NEJM) that provides clinical and radiological details on volunteers who were given consecutive daily doses of a drug being tested for safety as an analgesic and anti-inflammatory agent, possibly for neurologic pain. The experimental drug, which was referred to as BIA 10-2474, was a fatty acid amide hydrolase inhibitor intended to target the endocannabinoid system; the agent was manufactured by Bial, a Portuguese pharmaceutical company.
The case has been reviewed by French authorities, and those investigations have turned up some shortcomings in the clinical trial design and execution. But precisely how a drug that seemed to be safe in animal testing and other early testing in people turned out to be deadly is still unclear.
“An unanticipated severe neurologic disorder occurred after ingestion of BIA 10-2474 at the highest dose level used in a phase 1 trial,” said the NEJM report. “The underlying mechanism of this toxic cerebral syndrome remains unknown.”
Independent physicians and bioethicists interviewed by Neurology Today agreed that the case provides an opportunity to explore issues related to clinical trial design, informed consent, trial oversight, and the sharing and publication of early testing results. The question of potential risks versus benefits always needs to be carefully weighed, even in phase 1 trials where the emphasis is on safety not efficacy, they said. [For more on the principles deemed necessary for ethical clinical research, see “The 7 Ethical Requirements of Clinical Research.”]
As was the case with the French study, phase 1 studies typically involve healthy volunteers who have nothing to gain from the drug being tested. Other drug companies had tested molecules similar to BIA 10-2474 and abandoned their efforts due to insufficient evidence of efficacy, and even earlier findings on BIA 10-2474 were not impressive, noted Jonathan Kimmelman, PhD, associate professor in the biomedical ethics unit at McGill University in Montreal, who was not associated with that research.
“How did a drug that has so little promise make it into phase 1 studies? It's a little bit unsettling,” he told Neurology Today.
The untoward results occurred as part of a “first-in-human” phase 1 clinical trial in January involving eight people, six of whom received 50 mg daily of BIA 10-2474 and two of whom received placebo. According to an April report by an inquiry committee in France, a total of six volunteers were hospitalized with adverse events: one had neurologic symptoms on day five of drug administration, two on day six, two others on the day after the last day of drug administration, and one other had adverse effects two days after the last administration of the drug. The testing, which occurred as a clinical trial unit run by Biotrial, a drug testing company, continued even after volunteers began to be transferred to the hospital with neurologic symptoms.
The NEJM report, written by doctors at Rennes University Hospital in France, where the study participants were taken, contains details on four of the six volunteers (men aged 27 to 49 years) who were given the drug. (Only three volunteers and the family of the patient who died provided consent to be included in the report.)
“An acute and rapidly progressing neurologic syndrome developed in three of the four participants starting on the fifth day of drug administration,” the report noted. “The main clinical features were headache, a cerebellar syndrome, memory impairment, and altered consciousness.”
Radiologic findings were also indicative of neurologic problems. “Magnetic resonance imaging showed bilateral and symmetric cerebral lesions, including microhemorrhages and hyperintensities on fluid-attenuated inversion recovery and diffusion-weighted imaging sequences predominantly involving the pons and hippocampi.”
A SUCCESSION OF PROBLEMS
The journal report provided details on how a seemingly routine drug trial turned bad. For instance, on day five, the volunteer who was ultimately declared brain dead reported moderate blurred vision and floating specks, followed by headache, gait disturbance, and slurred speech. By day seven, his heart rate was below 40 beats per minute and he was hypotensive. On that same day, another volunteer who had continued to be administered the drug despite what in hindsight were red flags began asking the same questions repeatedly about recent activities and was transferred to the hospital.
Another volunteer reported mild asthenia, headache, and dizziness on day five but was found to be normal on a neurologic exam at the testing unit. He was finally transferred to the hospital on day eight, when he presented with “a subacute gait disturbance, slurred speech, and a syncope,” the report said.
“One patient became brain dead; the condition of two patients subsequently improved, but one patient had residual memory impairment and the other patient had a residual cerebellar syndrome. One patient remain asymptomatic,” the doctors wrote of the four cases they presented in the journal article. They did not have access to the autopsy report on the patient who died.
They said the clinical and radiologic findings “suggest direct toxicity of BIA 10-2474,” likely due to the cumulative high dose acquired by the volunteers as the trial progressed. They noted that while the drug was meant to target the endocannabinoid system, the toxicity might have been caused by an “off-target” effect that remains to be identified.
Susana Vasconcelos, a spokesperson for Bial, told Neurology Today that the company “continues to carry out all efforts to understand what happened in the clinical trial.” She said the company “decided to discontinue the research with this molecule for commercial purposes.”
She noted that the case has been investigated in France by the Inspection Géneralé des Affaires Sociales and the Temporary Specialist Scientific Committee. A baffling part of the BIA 10-2474 story is that the drug did not appear to have worrisome side effects during prior testing, according to investigative reports. Before the testing in the eight volunteers — six received the active drug, two the placebo — the compound had been tested in 84 other healthy volunteers.
An editorial that accompanied the report in the NEJM said the drug trial underscores the need for constant refinement of clinical trial protocols.
“Lessons learned by failures of and adverse events in clinical trials should help regulators develop strategies to make drug development safe,” wrote Sergio Bonini, MD, and Guido Rasi, MD, of the European Medicines Agency.
Dr. Kimmelman said that even researchers involved in clinical trials may have incomplete information about potential safety and efficacy issues because early testing data are rarely published or shared among the scientific community.
“A lot of information we need to assess safety sits in the filing cabinets and hard drives of companies,” he said. “With disclosure of early results, we could be learning a lot more and protecting patients better.”
THE WARNING SIGNS
Michael A. Williams, MD, FAAN, professor of neurology and neurological surgery at the University of Washington, said that early phase clinical trials “first test safety, and then efficacy, and that the risk-benefit ratio for the research participants depends on the circumstances.” Phase 1 trials, in which healthy volunteers have no expectation of benefit from a drug, as was the case in France, “are the only types of trials in which risk without benefit is ethically permissible, as long as the participants are informed and appropriate safeguards are in place,” he said. “In phase 2 trials involving patients, however, the expectation is that some degree of benefit, albeit unproven, should exist to balance the risk of participating in the trial, as long as safeguards exist.”
Dr. Williams said the unfortunate outcome in the French trial should be a reminder to researchers conducting drug testing that they may have conflicting duties as researchers and clinicians. “You not only have to pay attention to the rules of the protocol to complete the clinical trial, but you also have to use clinically-guided common sense to know when to stop,” he said. He said a key criticism of the French trial has been that “they should have stopped it as soon as the first participant developed severe symptoms.”
Dr. Williams, who formerly was the chair of the AAN Ethics, Law and Humanities Committee and whose research interest is hydrocephalus, said the design of the clinical trial would have been safer if the schedule for the participants at a given dose had been staggered, and if a built-in hard stop for all participants was required in the event of any serious unexpected symptoms, rather than administering the drug to all participants simultaneously day after day, even after the first serious adverse events emerged.
Another key consideration in human testing is to ask, “What have we learned so far before we go up to the next dose?” he said. He added that the 50 mg daily dose used in the French trial may not have been justified based on reports of the previous testing and the pharmacokinetics of the drug.
SAFE ISN'T GOOD ENOUGH
Eran Klein, MD, PhD, a neurologist and ethicist in the department of neurology at Oregon Health and Science University, agreed that study participants would be better protected if researchers shared their findings from early-stage research and failed trials.
“We focus so much on the risk, but without an understanding of potential benefits of a drug relative to others in the marketplace it is hard to know how to balance this risk,” Dr. Klein said. “Just because a drug is a little bit better than something else does not mean it merits development.” He added that in the case of painkillers, “worries over the opioid epidemic should not drive down scientific standards.”
Dr. Klein said he hoped the French trial serves as a wake-up call to researchers conducting clinical trials and those in the laboratory doing basic science. He said understanding the mechanics of how a drug works is critical to assuring its safety.
“I worry that our science is becoming complacent,” he said. “This is a painful but important reminder that we have an obligation to people who volunteer for clinical trials and owe them our utmost diligence to protect them.”
THE 7 ETHICAL REQUIREMENTS OF CLINICAL RESEARCH
Bioethicist Ezekiel J. Emanuel, MD, PhD — the founding chair of the department of bioethics at the National Institutes of Health until 2011 and currently the vice provost for global initiatives and chair of the department of medical ethics and health policy at the University of Pennsylvania — and colleagues proposed seven requirements for evaluating the ethics of clinical research studies in a 2001 paper in the Journal of the American Medical Association. These principles, leading researchers say, still apply, especially in the context of the current New England Journal of Medicine study.
- Value: Enhancements of health or knowledge must be derived from the research
- Scientific validity: The research must be methodologically rigorous
- Fair subject selection: Scientific objectives, not vulnerability or privilege, and the potential for and distribution of risks and benefits, should determine communities selected as study sites and the inclusion criteria for individual subjects
- Favorable risk-benefit ratio: Within the context of standard clinical practice and the research protocol, risks must be minimized, potential benefits enhanced, and the potential benefits to individuals and knowledge gained for society must outweigh the risks
- Independent review: Unaffiliated individuals must review the research and approve, amend, or terminate it
- Informed consent: Individuals should be informed about the research and provide their voluntary consent
- Respect for enrolled patients: Subjects should have their privacy protected, the opportunity to withdraw, and their well-being monitored.