News Article | January 16, 2016
On Friday several French agencies opened an investigation into a clinical drug trial that has hospitalized six men in the last week, leaving one permanently brain dead and three in critical condition, likely with permanent brain damage. At a press conference held Friday afternoon at the University Hospital of Rennes, where the six victims are currently being treated, the French Minister of Health, Marisol Touraine, vowed to “get to the bottom of this…tragic incident.” She also denied reports that the experimental drug contained cannabis or cannabis derivatives, as some French media agencies had originally reported. When the story of the hospitalizations broke, several French media agencies erroneously reported that a “cannabis based product was in question” and i-Télé reported that a cannabis-based pain killing drug was being injected into the trial participants. This assertion was categorically denied by Touraine during her press conference. “Contrary to what I've heard, this drug does not contain cannabis and is not a cannabis derivative,” said Touraine. “It acts on the endo-cannabinoid system.” The confusion likely stems from the use of the word ‘cannabinoid,’ the term for a wide variety of compounds which act on the cannabinoid receptors in the brain. These cannabinoid receptors are part of the endocannabinoid system, which is found in a wide variety of mammals and is responsible for helping regulate everything from memory and pain to appetite and mood. There are three major types of cannabinoids: endocannabinoids (produced naturally in humans and animals), synthetic cannabinoids (manufactured artificially) and phytocannabinoids (which are found naturally in some plants, such as cannabis). Although tetrahydrocannabinol (also known as THC, the main psychoactive compound in cannabis) is perhaps the most well-known cannabinoid, it is not a part of the drug that was being tested in Rennes. Just which molecule was being tested is not known for sure: a press release from Bial, the Portuguese pharmaceutical company that produced the drug in question, described the molecule as a type of pain medication known as an FAAH enzyme inhibitor. There is a chance the molecule was BIA 10-2474, an experimental drug for “neurological and psychiatric pathologies” and one of two substances listed on Bial’s website as in the first phase of clinical trials. The clinical trial for the molecule that has left six men, ages 28-49, with varying degrees of neural complications (one brain dead, three in critical condition, one with neurological problems and one under close observation) began last year in July. It has been executed by Biotrial, a research company operating on behalf of Bial. So far the molecule has been administered to a total 90 participants, although the six hospitalized last week were the first to show such severe adverse effects. The six men began taking the molecule on January 7, and by January 10 the first man was hospitalized and his condition rapidly deteriorated until he was declared to be brain dead by Gilles Edan, the chief neuroscientist at the Rennes hospital. According to Edan, there is no known antidote to the compound. This calamitous occurrence is a first for France, which maintains strict national and international regulations for carrying out drug testing on humans. Typically, a drug undergoing a clinical trial goes through three phases. In Phase I, the drug is administered to healthy patients in incremental doses—the first patients will receive a single dose while latter patients will receive multiple doses over several days. In Phase II, experimental drugs are given to patients with relevant conditions to see if the drug helps them. In Phase III, the drug is tested against a placebo and compared with existing treatments to gauge its effectiveness. The six hospitalized participants were participating in the first phase of the clinical trials for this molecule and were all declared healthy prior to beginning the study. According to Bial’s press release, the company had the clinical trial approved by the French Regulatory Authorities as well as the French Ethics committee in accordance with the guidelines laid out in Good Clinical Practices and Declaration of Helsinki. The trials related to the Bial drug have been suspended as of January 11 and at her press conference Touraine promised a full scale investigation into the trial spearheaded by the French General Inspectorate of Social Affairs. The Health Minister said she expected a final report on the occurrence by the end of March at the latest.
Six medical volunteers have been hospitalized - one in a state of brain death - after taking part in a botched drug test at a clinic in western France, the Health Ministry said Friday. The prosecutor's office has opened an investigation into what the ministry called a "serious accident during a clinical test" in Rennes. It did not name the clinic. However, the Rennes-based lab Biotrial said its CEO, Jean-Marc Gandon, would join Health Minister Marisol Touraine. The minister went to Rennes on Friday after ordering an investigation into the organization and how it conducts clinical tests. The ministry statement said those who fell ill had taken an oral medication in the first phase of testing, which was studying safe usage, tolerance and other measures on healthy volunteers. It was not immediately clear whether the six were among a larger group of volunteers involved in the tests or what dose they had been given. The statement did not name the type of medication being tested. Biotrial, with headquarters in Rennes and offices in London and Newark, New Jersey, says on its website it has over 25 years of experience in clinical trials and uses "state-of-the-art facilities." In France, adults volunteering for Biotrial tests can earn between 100 euros and 4,500 euros ($110 to $4,922). It is rare for volunteers to fall seriously ill when testing new drugs. Researchers generally start with the lowest possible dose for humans after extensive drug tests in animals. But there was a similar incident in Britain in 2006, when six previously healthy men were treated for organ failure only hours after being given an experimental drug targeting the immune system. That prompted a review of procedures and resulted in the U.K. regulatory agency imposing new testing standards, including recommendations to use the lowest possible dose and to test new drugs only in one person at a time. The six men in Britain now apparently have a higher risk of cancer and autoimmune diseases tied to their exposure to the experimental drug. Dr. Ben Whalley, a neuropharmacology professor at Britain's University of Reading, said standardized regulations for clinical trials are "largely the same" throughout Europe. "However, like any safeguard, these minimize risk rather than abolish it," Whalley said in a statement. "There is an inherent risk in exposing people to any new compound."
The clinical trial, conducted by the company Biotrial on behalf of the Portuguese pharmaceutical firm Bial, was evaluating a pain relief drug candidate that inhibits fatty acid amide hydrolase (FAAH) enzymes. Blocking these enzymes prevents them from breaking down cannabinoids in the brain, a family of compounds that includes the euphoria-inducing neurotransmitter anandamide and Δ9-tetrahydrocannabinol, the major psychoactive component of marijuana. Phase I clinical trials are conducted to check a drug candidate’s safety profile in healthy, paid volunteers. In this case, the drug caused hemorrhagic and necrotic brain lesions in five out of six men in a group who received the highest doses of the drug, said Gilles Edan, a neurologist at the University Hospital Center of Rennes, during a press conference on Friday. All six men were hospitalized by Sunday, Jan. 10, and the clinical trial was stopped the next day. The most severely affected man was pronounced brain dead after hospitalization and then died on Jan. 17. Prior to these serious adverse reactions, 84 people had taken lower doses of the candidate drug without complications, a hospital press release stated. Over the weekend, ten of those 84 individuals were given MRI scans. The hospital reported that none of the brain anomalies seen in the hospitalized patients were observed in these low-dose trial participants. A spokesperson for the European Medicines Agency told C&EN that “since 2007, approximately 12,500 Phase I clinical trials have been conducted in the European Union without any major incidents being reported.” The last major Phase I clinical trial catastrophe took place in London in 2006, when six healthy men suffered permanent organ damage, including loss of fingers, during a trial for an immunotherapy drug candidate called TGN1412. In the case of TGN1412, within minutes of being given the putative arthritis and cancer drug, the volunteers suffered from unanticipated and severe immune reactions. An analysis of the 2006 tragedy concluded that “drugs showing safety and efficacy in preclinical animal models may show very different pharmacological properties when administered to humans. Development of proper preclinical models which can efficiently predict drug behavior in humans is very essential prior to testing a drug in a human subject” (J. Young Pharma 2010, DOI: 10.4103/0975-1483.66810). French authorities have now launched several investigations to determine whether the Bial clinical trial was conducted properly and whether there were problems with the manufacture or transport of the drug candidate. In a press release, Bial officials noted that the clinical trial “has been conducted since the beginning in accordance with all the good international practices guidelines, with the completion of tests and pre-clinical trials, particularly in the area of toxicology.” Multiple pharmaceutical companies, including Merck & Co. and Pfizer, have evaluated FAAH inhibitors as possible treatments for pain, anxiety, and insomnia, among other applications. Until the current tragedy in France, there have been no reports of extreme adverse reactions for FAAH inhibitors. A Phase II clinical trial conducted by Pfizer to evaluate an FAAH inhibitor for post-traumatic stress disorder, for example, was terminated “based on Pfizer portfolio prioritization and not due to safety and/or efficacy concern,” noted an entry on clinicaltrials.gov. As the news of the clinical trial broke, the online chemical community exploded with speculation about the nature of the putative drug. To date, the company has reported only that it is an FAAH inhibitor developed for pain remedy. Many observers, however, believe the compound’s name is BIA 10-2474. That’s because the company’s website lists two drug candidates in Phase I clinical trials. One candidate is for pulmonary arterial hypertension—a drug that likely targets the lungs instead of the brain and is therefore unlikely to be an FAAH inhibitor. The second Bial candidate—BIA 10-2474—is listed for “neurological and psychiatric pathologies,” and is thus more likely to be involved in the tragedy. Additional support for BIA 10-2474 being the compound’s name comes from an e-mail forwarded to the French news outlet Breizh-info.com from a man who had tried to enlist in the trial but was denied entry. Southan has mined the patent literature and thinks he may have figured out the drug candidate’s structure. He says the trick is to look at secondary patent filings. Companies tend to protect a whole series of molecules in their first patent filings without naming their most promising lead compound, Southan explains. In subsequent patents for processing, synthesis, or crystallization techniques, though, it’s possible to surmise which compound is destined for the clinic, he says. In this case, Southan found a 2014 patent in Bial’s portfolio that he thinks is a “best guess” for the lead compound involved in this clinical trial. Minutes before he posted a blog post reporting his patent mining for BIA 10-2474, Southan says an anonymous Wikipedia editor posted the same structure in the online encyclopedia, giving him confidence that he was on the right track. Others in the online chemical community have since evaluated the structure proposed by Southan and the anonymous Wikipedia editor for binding partners in the body other than FAAH enzymes. If the drug candidate hits “off target” partners, it might help explain what went wrong with this trial. For example, computational chemist Sean Ekins, from Collaborative Chemistry, inputted the putative structure for BIA 10-2474 into an in silico screening app called PolyPharma that searches for possible biological targets of a submitted molecule. He also ran the molecule through another ligand-protein modeling program called SEA, developed independently by Brian Shoichet at the University of California, San Francisco.
Sibille M.,Center Hospitalier Lyon Sud |
Patat A.,Biotrial |
Caplain H.,Sanofi S.A. |
Donazzolo Y.,Optimed Clinical Research
British Journal of Clinical Pharmacology | Year: 2010
Aim: To propose a relevant grading scale for clinical adverse events or laboratory results, electrocardiogram (ECG) and vital sign findings supporting both dose escalation and stopping decisions in first-entry-into-man (FIM) studies conducted in young healthy subjects. Methods: A three-level scale was used for the proposed grading system. The grading is directly derived from the observed severity of discontinuous variables, as are most of clinical adverse events. A 'combined method' based on normal ranges and spontaneous variation is suggested for grading the findings which are continuous variables mainly numerical in nature. One grade, at the subject level, and one algorithm, at the cohort level, support the proposed decision rules. This work was managed by a Club Phase I working group. Results: Examples of grade 1, 2 and 3 limits are given for the most frequent clinical adverse events and laboratory tests, ECG and vital sign findings. When available, the proposed NIH and FDA limits are also provided. The safety recommendation is to use the grade 2 at least as an alert for caution and the grade 3 as a maximum for stopping, applying the algorithm at the cohort level. Conclusions: This paper proposes a safety grading system based on relevant criteria which might be used by investigators and sponsors to support and rationalize dose escalation decisions in healthy young subject FIM studies. These proposals are designed not to be a guideline but some 'points to consider' helping the dose escalation process. This paper supports the recent reinforcement of the safety requirements for FIM studies by European authorities. © 2010 The Authors British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society. Source
One man is dead and five men were hospitalized after participating in a Phase I clinical trial in Rennes, France. The clinical trial, conducted by the company Biotrial on behalf of the Portuguese pharmaceutical firm Bial, was evaluating a pain relief drug candidate called BIA 10-2474 that inhibits fatty acid amide hydrolase (FAAH) enzymes. Blocking these enzymes prevents them from breaking down cannabinoids in the brain, a family of compounds that includes the euphoria-inducing neurotransmitter anandamide and Δ9-tetrahydrocannabinol, the major psychoactive component of marijuana. Phase I clinical trials are conducted to check a drug candidate’s safety profile in healthy, paid volunteers. In this case, the drug caused hemorrhagic and necrotic brain lesions in five out of six men in a group who received the highest doses of the drug, said Gilles Edan, a neurologist at the University Hospital Center of Rennes. The most severely affected man was pronounced brain-dead after hospitalization and then died on Jan. 17. Four men remain in the hospital in stable condition. The only man in the high-dose group who had no adverse symptoms has been released from the hospital. Prior to the hospitalizations, 84 people had taken lower doses of BIA 10-2474 in the clinical trial without complications. A spokesperson for the European Medicines Agency told C&EN that, “since 2007, approximately 12,500 Phase I clinical trials have been conducted in the European Union without any major incidents being reported.” The last major Phase I clinical trial catastrophe took place in London in 2006, when six healthy men suffered permanent organ damage, and the loss of fingers, from unanticipated severe immune reactions during testing of an arthritis and cancer drug candidate called TGN1412. Multiple pharmaceutical companies, including Merck & Co. and Pfizer, have evaluated FAAH inhibitors as possible treatments for pain, mood disorders, and insomnia, among other applications, with no reports of significant adverse reactions until the Bial clinical trial. After the events in Rennes, Janssen, part of Johnson & Johnson Pharmaceutical Research & Development, voluntarily suspended a Phase II clinical trial of an FAAH inhibitor; no adverse events have been reported, the company noted in a press release, so it was a precautionary step . As news of the clinical trial tragedy broke, the online chemical community exploded with speculation about the nature of the putative drug. “What everybody wants to know now is its structure,” says Christopher Southan, a senior curator for the University of Edinburgh-based Guide to Pharmacology database. As C&EN went to press, Le Figaro posted a 96-page clinical study protocol for BIA 10-2474 that the French newspaper procured from an unnamed source. BIA 10-2474 “is designed to act as a long-active and reversible inhibitor of brain and peripheral FAAH,” notes the protocol. The compound “increases anandamide levels in the central nervous system and in peripheral tissues.” The clinical trial protocol also notes that the company tested BIA 10-2474 on mice, rats, dogs, and monkeys for effects on the heart, kidneys, and gastrointestinal tract, among other pharmacological and toxicological evaluations.