On Jan. 1, 2016, clinical researchers heard news that they dread: Healthy volunteers in a drug trial experienced serious side effects. One volunteer in the French trial died and five others were hospitalized with neurological symptoms. Questions now remain as to how this happened and how the tragedy will affect clinical trials in Europe and in the United States.

The compound being studied, BIA 10-2474, was developed by Bial, a Portuguese pharmaceutical company, and was being studied by contract research organization (CRO) Biotrial in Rennes, France. Based on information in the trial protocol, BIA 10-2474 is an experimental fatty acid amide hydrolase (FAAH) inhibitor. Documents from a prospective volunteer forwarded to French media described BIA 10-2474 as a "product in development for the treatment of different medical conditions from anxiety to Parkinson's disease, but also for the treatment of chronic pain of sclerosis, cancer, hypertension, or the treatment of obesity.”1 The drug is intended to affect the endocannabinoid system, brain receptors that deal with pain.

Details of the trial

The Phase 1 trial used healthy volunteers, men and women between the ages of 18 and 55.  According to information from the French National Agency for Medicines and Health Products Safety (ANSM), the trial had these objectives:

• the safety and tolerability of BIA 10-2474 after single and multiple oral doses;
• the effect of food on the pharmacokinetics (PK) of BIA 10-2474;
• the pharmacokinetics (PK) and pharmacodynamics (PD) profile of BIA 10-2474.2

The trial recruited 128 volunteers. Ninety received different doses of the drug. The rest received a placebo.3

The trial protocol spelled out three parts of the trial. The first was the administration of single-ascending doses of the investigational medicinal product (“verum”) or placebo. ANSM documents show eight ascending doses were tested, each dose being tested in a cohort of eight volunteers (64 subjects total).2 No adverse events were noted in this part of the trial. The second part involved a cohort of 12 volunteers receiving on two occasions one 40 mg verum dose, once in the morning on an empty stomach, and once after a “fat-rich breakfast.” Again no adverse events were noted.

The third part of the trial involved the administration of multiple-ascending doses. Eight ascending doses were tested, each dose being tested in a cohort of eight volunteers. Two volunteers in each cohort were given placebo. On Wednesday, Jan 6, 2016, the fifth cohort began treatment with 50 mg dose of the verum (19 days after the end of cohort 4). Sunday, January 10, was the fifth day of administration to the eight male volunteers of a 50 mg dose. A volunteer was hospitalized in the evening with “stroke-like” neurological symptoms.
The remaining seven volunteers received a sixth treatment dose the next morning. The first volunteer, who had now lapsed into a coma, received an MRI. The results of the scan showed deep hemorrhagic and necrotic lesions. The sponsor and Biotrial then agreed to discontinue the trial, and the hospitalized volunteer was said to be brain-dead. By Friday, January 15, five other volunteers treated with the verum in that cohort had been hospitalized with similar neurologic symptoms. Biotrial advised ANSM of the adverse effects on January 14. None of the remaining volunteers have shown neurological symptoms similar to those hospitalized.

Initial reaction from the tragedy

On January 17, Bial issued a statement announcing the death of the volunteer, saying the company’s “thoughts and solidarity” go out to his family.4 On January 19, Bial issued a new release saying it “deeply regrets the death of one of the volunteers participating in the trial.”5 According to Bial, the “project of investigation” was initiated in 2005, and studies with this compound began in 2009 with preclinical in vitro and in vivo pharmacological and toxicological evaluation. “The results obtained in these preclinical studies have shown a safety and tolerability profile that allowed, in June 2015, the approval of the Phase 1 clinical trial in humans with healthy volunteers by the French Regulatory Authorities and by the French Ethics Committee, in accordance with Good Clinical Practices, with the Declaration of Helsinki and the inherent clinical trials related legislation.”

Until the trial’s protocol was released by a French publication on January 21 and then by ANSM, speculation was high as to the type of compound involved in the study.  The research community still wanted additional information after the release of the protocol, however. On January 22, the United Kingdom’s Royal Statistical Society (RSS) in London called for three more disclosures from the trial:6

• The investigator brochure (minimally redacted). The brochure, RSS says, usually describes preclinical studies in detail and needs to be put into the public domain.
• The escalated dose levels. RSS wants the levels that were actually tested in the trial’s single-administered dose phase, together with the number of volunteer cohorts on whom each dose level was tested. “We note that backtracking to re-test a dose level was allowed as well as escalation,” RSS says.
• The regimen actually selected for 10 days’ administration to first cohort of healthy volunteers in the trials multiple-administered dose phase.
• “Our thoughts are with the families of all the men in the affected cohort. Key recommendations in the RSS report cover proper risk assessment, sharing that assessment with all parties, and the sharing of information across studies to improve the assessment of risk,” says Stephen Senn, professor at the School of Mathematics and Statistics at the University of Glasgow. “We hope that, as the inquiry proceeds, these matters will be properly and expertly addressed not only by physicians but also by statisticians.”

Bial has cited French laws that protect the release of trade secrets in its reluctance to publish the brochure and another document, says ANSM.3 The drug company’s disclosures were questioned again when information came out about the drug being tested on animals. According to the trial protocol, animal toxicology studies of repeated daily dosing of BIA 10-2474 for up to 13 weeks in mice, dogs, and monkeys and up to 26 weeks in rats, had been conducted. In dogs, BIA 10-2474 “had no major effects on arterial blood pressure (BP), heart rate, and on the PR, the QRS, the QT and the QTc (Fridericia's and van de Water's formulae) intervals. No arrhythmia or other changes in the morphology of the electrocardiogram which could be attributed to BIA 10-2474 were observed,”7 the protocol says.

However, French newspaper Le Figaro says it has information that a number of dogs died or had neurological damage from pre-clinical testing with the compound.8 François Peaucelle, director of Biotrial, told French news channel BFMTV that the death of the dogs was not significant. “The conclusions of this study were sufficiently clear and clean to rule out any particular ambiguity about proceeding with human tests.”9 Biotrial, which also did the testing on the dogs, and France’s drug safety agency say details of earlier testing of the molecule cannot be published because of industrial secrecy, United Kingdom’s The Guardian says.

ANSM updates investigation

On February 1, ANSM released an update on its investigation on determining the factors that led to the accident.10 This analysis supplements other investigations led by judiciary authorities, the French General Inspectorate of Social Affairs, and the Ministry for Health.

As part of its investigation, ANSM says it would:

• Continue the inspection work that the agency has performed on the site of the research center in Rennes.
• Search for the medical causes that led to the death of one of the volunteers and serious consequences for the four others. The agency says it has appointed clinical experts in charge of analyzing the available medical data gathered to date.
• Create a temporary specialist scientific committee that includes French and European toxicology and pharmacological experts and clinicians. The committee is tasked to explore “all the pharmacological and toxicological hypothesis that could have led to this accident.” The committee was created on January 21and was to meet on Feb. 15.

Clinicians watching news of this trial said the timeline shows that the BIAL researchers were not using the recommendations of the European Medicines Agency (EMA). After six men had serious adverse reactions from a trial in United Kingdom, EMA recommended that adequate time intervals be used between the dosing regimens on study participants. This allowed researchers to monitor the participants for possible side effects before giving the drugs to other patients. When asked if EMA may revise its clinical trial standards as a result of the BIAL adverse effects, EMA says it will be reviewing ANSM’s findings. “The French authorities have opened an investigation including verification that the clinical trial has been carried out according to standards,” EMA spokeswoman Rebecca Harding told journalists. “EU [European Union] authorities will look carefully at the findings to determine if further measures are needed to protect health of clinical trial participants. Until EU authorities have the full picture, it is not possible to say whether any revisions to EU guidelines are required.”11

IGAS issues prelim report

In early February, France’s General Inspectorate of Social Affairs (IGAS) issued a preliminary report on the drug trial events. A full report is expected at the end of March. In this report, IGAS shines a light on Biotrial saying that the CRO made three major errors that put the study volunteers at risk.12

First of all, volunteer “2508” was taken to the hospital early Sunday evening after complaining of headaches and blurry vision. The next morning, the Biotrial staff gave the remaining volunteers their daily dose of the verum without first checking on the status of the hospitalized volunteer, the IGAS report says. Staff members say they expected to hear from the hospital or have the volunteer back in the study. At 9 a.m., the hospital told a Biotrial doctor that the volunteer’s condition had worsened and he had been sent to get an MRI test. He was subsequently declared brain-dead. The four other volunteers became ill as well and were hospitalized. The trial was halted that day.12

Biotrial was also faulted in the report for not giving information to the remaining volunteers Monday morning about volunteer 2508 being hospitalized. This kept them from being able to reconsider their participation in the study. “This violated what Biotrial had promised in an informed consent form: ‘You will be informed about any new significant information that could affect your willingness to continue the trial.’" In addition, IGAS says Biotrial waited too long to notify ANSM, 3 days after the termination of the study. “That made it impossible for ANSM to take measures to protect volunteers who took part earlier or those enrolled in other studies of the same class of molecules,” the report says.12

French health minister Marisol Touraine says that any hospitalization during a clinical trial should be regarded as "new fact that needs to be brought to the attention of health authorities immediately.”12 Such events should "lead to an immediate suspension of the trial until the safety of volunteers is guaranteed," she says. "Volunteers must be clearly informed about the suspension of the study and its reasons."

Biotrial issued a statement on February 4 about the report, saying it was “unfortunate” to find out about it from the press.13 “Biotrial is relieved that the IGAS status report confirms that the center is not accountable for the volunteer’s death, and that no fault has been identified in the accident that took place during the clinical trial of the molecule from the Portuguese pharmaceutical laboratory, Bial,” the statement says. “Biotrial reaffirms having strictly applied the precautionary principle and having rigorously complied with the protocols, in accordance with international standards that govern clinical trials – more specifically in regards to the timing of the pursuit of the trial, its suspension, and its definitive termination after the volunteer (who has since died) was hospitalized.”  

Biotrial pushed back on the IGAS timeline, saying it had no reason to believe the hospitalized volunteer had more than “light symptoms” when it gave the additional volunteers the next dose. “In this context, given the information on the medical condition of the hospitalized patient and in compliance with the rules governing clinical trials, suspension of the trial was not justified. An additional administration of the tested product was therefore administered at 8:00 a.m. to the other volunteers,” the statement says. “At9:00 a.m., Biotrial learned that the hospitalized volunteer was undergoing an MRI scan, and at 10:00 a.m., was told that he had suffered a stroke (CVA). Though this diagnosis seemed disconnected from the clinical trial, Biotrial and the Portuguese pharmaceutical laboratory Bial decided, as a precaution, to suspend the administration of the product. There was therefore no further administration of the product after 8:00 a.m. on Monday.”13

After the condition of the volunteer became known, all remaining volunteers were kept under strict supervision, the statement says. “The alleged shortcomings identified in the IGAS status report were in no way the cause the serious adverse effects which followed the administration of the pharmaceutical product BIAL BIA 10-2474.”

The Aftermath

The remaining five volunteers who experienced adverse effects from taking BIA 10-2474 remain hospitalized at Rennes Hospital, four with neurological problems and possible irreversible brain damage. "Three [of the patients] have symptoms so severe that it leads us to worry that they will be disabled for the rest of their life. However, this prognosis is still not definitive,” says Gilles Edan, who leads the neuroscience department at Rennes.14

The French newspaper Le Figaro is demanding more information about the extent of the brain damage and is blaming ANSM for not providing it. ANSM president Dominique Martin would only tell journalists, "I can only say that the molecule has targeted an area at the base of the brain, but the rest is a medical secret.”13

French health minister Touraine says clinical trials in her county must continue. “There is a major problem — massive, unprecedented in France — and we must understand what happened, but there is nothing to justify stopping clinical trials," she says to France’s RTL radio. "A quicker alert would have been appreciated."15

The trial also brought focus on potential problems with FAAH inhibitors. In late January, Johnson & Johnson told Reuters in a statement that it had suspended international trials of a drug in the same class as BIA 10-2474. The statement says the company had not received reports of serious adverse events in its studies of patients with social anxiety disorder and major depressive disorder with anxious distress and would re-evaluate its decision when more information became available.16 More information may be available soon. The British Journal of Pharmacology is expected to publish an article in the March-April timeline that will address the trial, its transparency issues, and the mistakes made by Bial, Biotrial, and ANSM.

References

1. Brosky J, Sheridan C. Six hospitalized in Bial clinical trial in France. Bioworld Jan. 15, 2016. Available at http://www.bioworld.com/content/six-hospitalized-bial-clinical-trial-france-0. Accessed Mar. 1, 2016.
2. Chronology of the evaluation and performance of the clinical trial sponsored by BIAL laboratories and conducted by BIOTRIAL in Rennes. ANSM. Feb. 1, 2016 Available at: http://ansm.sante.fr/var/ansm_site/storage/original/application/2e76c2230971bbdeea94725c605468e4.pdf. Accessed Mar. 1, 2016.
3. Butler D, Callaway E. Scientists in the dark after French clinical trial proves fatal. Nature Jan, 18, 2016 Available at http://www.nature.com/news/scientists-in-the-dark-after-french-clinical-trial-proves-fatal-1.19189#/graphic. Accessed Mar. 1, 2016.
4. Pressroom. Bial. Jan. 17, 2016. Available at https://www.bial.com/en/pressroom.138/news.140/phase_i_clinical_trial_rennes.a558.html. Accessed Mar. 1, 2016.
5. News release. Bial Jan 19, 2016 Available at https://www.bial.com/imagem/News_Release_19012016.pdf. Accessed Mar. 1, 2016.
6. RSS statement on publication on the study-protocol BIA-102474-101 for the French “first-in-man” trial in healthy volunteers. Jan. 22, 2016. Royal Statistical Society Available at http://www.rss.org.uk/Images/PDF/about/press-releases/2016-01-22-rss-statment-BIA-102474-101-french-first-trial-in-healthy-volunteers.pdf. Accessed Mar. 1, 2016.
7. Clinical Study Protocol N° BIA-102474-101. Bial - Portela & ca, S.A. July 1, 2015. Available athttp://ansm.sante.fr/content/download/84681/1069223/version/1/file/protocole_BIAL_102474+101-22012016131259.pdf. Accessed Mar. 1, 2016.
8. Jouan A, Mascret D. Biotrial: de nouvelles révélations troublantes dans l’essai clinique mortel de Rennes. Le Figaro Feb.  24, 2016 Available at http://sante.lefigaro.fr/actualite/2016/02/24/24667-biotrial-nouvelles-failles-beantes-dans-lessai-clinique-mortel-rennes. Accessed Mar. 1, 2016.
9. Willsher K, French drug trial scandal: ‘dogs died in pre-clinical test’. The Guardian Feb 25, 2016. Available at https://www.theguardian.com/science/2016/feb/25/french-drug-trial-scandal-dogs-died-in-pre-clinical-test. Accessed Mar. 1, 2016.
10. Essai clinique Rennes : l’ANSM poursuit ses investigations. ANSM. Feb. 1, 2016. Available athttp://ansm.sante.fr/Dossiers/Essai-Clinique-Bial-Biotrial/Essai-clinique-BIA-102474-101-du-laboratoire-BIAL/%28offset%29/0. Accessed Mar. 1, 2016.
11. Brennan, Z. EMA will assess ANSM review of botched clinical trial in France. RAPS Jan, 19, 2016. Available at http://www.raps.org/Regulatory-Focus/News/2016/01/19/23925/EMA-Will-Assess-ANSM-Review-of-Botched-Clinical-Trial-in-France/#sthash.5fT5XjJ6.dpuf. Accessed Mar. 1, 2016.
12. Enserink, M. French company bungled clinical trial that led to a death and illness, report says. Science Feb, 5, 2016 Available at http://www.sciencemag.org/news/2016/02/french-company-bungled-clinical-trial-led-death-and-illness-report-says. Accessed Mar. 1, 2016.
13. IGAS status report: Clarifications rom Biotrial. Biotrial Feb. 4, 2016 Available athttp://www.biotrial.com/news/press-release-february-4th-2016.html. Accessed Mar. 1, 2016.
14. Surugue L. France drug trial: Evidence of deadly dog tests before fatal brain damage dose to human subject. International Business Times Feb. 25, 2016 Available at http://www.ibtimes.co.uk/france-drug-trial-evidence-deadly-dog-tests-before-fatal-brain-damage-dose-human-subject-1545941. Accessed Mar. 1, 2016.
15. Khan M. France drug trial: Health minister says drug trials should continue despite death. International Business Times Jan. 18, 2016 Available at http://www.ibtimes.co.uk/france-drug-trial-health-minister-says-medicine-trials-should-continue-despite-death-1538644. Accessed Mar. 1, 2016.
16. Beasley, D. J&J stops trials of drug similar to one linked to brain death in France. Reuters Jan. 22, 2016 Available at http://uk.reuters.com/article/uk-johnson-johnson-drugtrial-idUKKCN0V000X. Accessed Mar. 1, 2016.

By Sue Coons, MA

This article was reprinted from Research Practitioner, Volume 17, Number 2, March-April2016.