Stakeholders in the Medical research enterprise, in the European Union and in the U.S., claim that clinical trials conducted on human subjects adhere to strict safety standards.
“One of the things that sets clinical trials apart from other scientific experiments is the obligation for care. Investigators undertaking them have obligations to ensure that patients enrolled are adequately cared for, even if doing so conflicts with or is at odds with required data collection and treatment procedures, as set forth in the protocol for the trial.” (Institute of Medicine, Review of the Fialuridine (FIAU) Clinical Trials, 1995)
[Fialuridine (FIAU) experiment was sponsored by the National Institutes of Health in 1993. The experiment resulted in the death of five of the human subjects; while two others required liver transplants.]
BIA 10-2474 was a tragic drug experiment conducted in January, 2016. A healthy volunteer died; four others were severely harmed. In response, Jayne Lawrence, chief scientist of the Royal Pharmaceutical Society issued a statement:
“Those in charge of the trial would have had to have shown they had done everything they could to protect patient safety before the trial was allowed to go ahead.”
The facts that emerged refute that claim. Indeed, on June 14, 2016, French prosecutors in Paris announced they have started a manslaughter investigation into the fatal BIA -10-2474 drug experiment. (Read more, in-Pharma Technologist)
The trial tested BIA 10-2474, a drug developed by the Portuguese pharmaceutical company Bial aimed at a wide range of ailments including pain, hypertension, multiple sclerosis, obesity, and cancer.
“Le BIA 10-2474 est un produit en cours de développement pour le traitement de différentes affections médicales allant des troubles de l’anxiété à des troubles moteurs des maladies de Parkinson mais également dans le traitement des douleurs chroniques de la sclérose en plaques, au cancer a l’hypertension ou encore dans le traitement de l’obésité… (BreizhInfo,Jan 2016)
According to Bial’s website, the phase I testing targeted multiple disorders including neuro-degenerative diseases; it is a “candidate drug for neurological and psychiatric pathologies”.
The trial was conducted by Biotrial, a French-based private company licensed to conduct clinical trials of drug safety and tolerability in healthy volunteers.
Phase I studies are designed to test safety and tolerability of a new drug, as well as how fast the chemical is processed by the human body. Most of these studies are carried out by specialized for profit contract research organizations (CROs); the human subjects are usually healthy volunteers who receive modest financial compensation.
“Because Phase I trials are used to determine a drug’s toxic effects, they are inherently risky, as unexpected events can — and do — occur. These trials pose significant practical and ethical issues.” (Professor Carl Heneghan of Oxford University)
The journal SCIENCE published two consecutive early reports by Martin Enserink on January 15, 16, 2016:
“What we know so far about the clinical trial disaster in France”; “More Details Emerge on Fateful French Drug Trial” The patients were previously healthy volunteers who were used to test the toxicity and tolerability of a candidate drug. Science noted that details about the accident were slow to emerge.
“Biotrial, a well-known contract research firm established in 1989, put a one-paragraph notice on its website today that said, without providing details, that during a first-in-man study, “serious adverse events related to the test drug have occurred in some subjects.” (A few hours later, the company issued another statement saying: “Our thoughts go out to the volunteers and their families. We are working hand in hand with the Health Authorities to understand the cause of this accident.“)
Dr. Gilles Edan, the neurologist at the University of Rennes Hospital Center said MRI imaging had shown “deep, necrotic, and hemorrhagic lesions in the brain” of the patients. “One person is brain-dead and five more have been hospitalized after a phase I clinical trial in France went horribly wrong. At least three of the patients may suffer irreversible brain damage if they survive, a doctor treating them said today.”
“Investigators have faulted Biotrial for continuing to administer the test molecule, BIA 10-2474, to five others after the first volunteer was hospitalised with severe headaches. It was only after the first victim suffered a stroke that the tests were stopped.” (Irish Times, March, 2016)
The drug’s action is irreversible
A distinctive problematic issue is that the drug is an irreversible fatty acid amide hydrolase (FAAH) inhibitor, which means that the drug chemically bonds with the enzyme to inactivate it. Irreversible inhibitors are risky because any time a small molecule is designed to irreversibly bind to an enzyme, it may stimulate the immune system to mount an inflammatory response against it, and also against regions surrounding the enzyme to which the drug binds. This can result in a catastrophic autoimmune reaction in some individuals.
The first of six patients in the Bial study who arrived at the University of Rennes Hospital Center had developed “very severe symptoms” that neurologists led by Dr. Gilles Edan’s team initially thought might be caused by a stroke.
“The patient soon deteriorated further and is now brain-dead, Edan said. Four other patients have neurological symptoms of varying severity, he added, but are not in a coma. “Of these four, three already have a severe enough clinical picture to fear that even in the best situation there will be an irreversible handicap,” Edan said. Because the drug’s effects on humans are unknown, the patients need to be monitored very closely, he said. “We cannot make a definitive prognosis.” The sixth patient does not have symptoms but is under surveillance.
All six men in the study who received multiple daily doses of the drug had been healthy volunteers between the ages of 28 and 49. The experiment was approved by the French National Agency for Medicine and Health Products Safety (ANSM) on 26 June 2015 without proper review of the risks involved. According to French health minister Marisol Touraine, the approved plan was to enroll 128 volunteers aged between 18 and 55 who would first test a single dose, then multiple doses, and finally the combination of the drug with a meal.
According to Ms.Touraine, 90 people had received varying doses of the drug while others had received a placebo. However, the six volunteers who were hospitalized all received multiple daily doses of the drug; the first one was given on January 7th and the first symptoms appeared on January 10th.
Human volunteers were deceived: Survivor of Lethal French Drug Trial Speaks Out
Stéphane Schubhan (42), a professional photographer, was a subject in the BIA 10-2474 lethal experiment. He does not know if he can ever work again.
When Schubhan reported suffering from headaches on January 11th, four days after the tests started, Biotrial’s doctors gave him paracetamol. The following day, his eyelids turned black. They added an ice pack.
When he tried to get up on January 13th, he could see nothing, felt dizzy and fell. Schubhan was taken to Rennes hospital. “The scan showed blood stains and white streaks on my brain,” Schubhan described. The experimental drug caused lesions in the hippocampus, the central lobe of the brain.
The following day, doctors advised his companion to bring their children to see him, “just in case”.
“Schubhan sleeps badly, has nightmares, sees double at all times, walks with difficulty, and succumbs to dizziness and nausea if he stands more than 10 minutes at a time. Doctors say they hope his condition will improve in six months to a year, but they are not certain.
“They didn’t tell us the truth about the dogs,” Schubhan said. “If I’d known the dogs were dead, I wouldn’t have risked my life for €1,900. I wouldn’t have signed up. I’m not crazy.” (Irish Times, March 2016)
Speculations about the cause of the severe symptoms include the fact that these six men were the first to receive multiple doses of the drug. Another possibility is a dosing accident, where patients were given far higher dosage than clinicians thought; the possibility that a batch of the drug was contaminated was also speculated.
Forbes contributor, David Kroll notes that whereas most drug hypersensitivity reactions occur in the liver, the skin, and in the bone marrow… BIA 10-2474 caused brain damage – which is unusual. He cites scientists who pointed to the possibility of
“off-target effects that may have led to brain injury…the drug may have had effects on an unintended biochemical process.” FAAH belongs to a family of 200 enzymes called serine hydrolases, some whose function is not yet understood…the drug might bind to other cellular proteins that affect blood flow in the brain.”
An information sheet for prospective human subjects is posted at the French regional news site Breizh-info.com. It provides an overview of the study’s goal and procedures (in French) and also offers a glimpse of what it’s like to partake in a lengthy drug safety study.
According to the document, the trial enrolled nonsmoking men and women aged between 18 and 55 who had a body mass index between 19 and 30. Participants in this particular experiment were to receive €1900, including travel expenses; in return, they agreed to stay at Biotrial’s facility in Rennes for 2 weeks, swallow a drug – BIA 10-2474 – on 10 consecutive days, undergo extensive medical tests, and provide at least 40 blood samples.
Prosecutors in Rennes opened an investigation and the French National Agency for Medicine and Health Products Safety (ANSM) conducted a confidential investigation as well. On May 23, 2016, the French Special Scientific Committee (CSST) panel of “experts” issued its final report after deliberating for 600 hours. The report noted the inaccuracy of documents submitted by Bial when seeking approval of the experiments.
The French daily, LeFigaro discredited the CSST report as a bureaucratic whitewash: the CSST report avoided all crucial scientific and safety issues and determined that that ANSM, which had approved the experiment, was without blame. Yet, the main problem inherent in the protocol was the rapid progression in escalating doses given to the subjects.
“The trial was designed so that six doses (2,5 mg ; 5 mg ; 10 mg ; 20 mg ; 50 mg and 100 mg) would be tested on one group of volunteers. The logic was to multiply the quantity, by two, each time a new dose was administered. This gradual progression is, however, not applied between dosages of 20 mg and 50 mg.” (International Business Times, April, 2016)
LeFigaro put the blame where it belongs: “blame the molecule, not the people that should have ensured this molecule went nowhere near a human…
A rough translation:
The preclinical toxicity data was ignored, the irreversible nature of the drug was ignored – the real tragedy is that the manufacturer did not do more preclinical work to consider how the compound was causing the animal toxicity.”
Trade secrets trump transparency and safety in experiments involving human subjects
Le Figaro reported that the confidential ANSM report was much more severe than the official National Agency for the Security of Medication report which refused to reveal the facts because of “industrial secrecy” laws. The official report exonerated ANSM and ignored the most important safety issues.
The manufacturer Bial refused the request by the French National Agency for Medicine and Health Products Safety (ANSM) to release the Investigator’s brochure and product dossier (IMPD) citing French law protecting trade secrets. (Wikipedia, note 17). The IMPD is the complete documented description of the product and all its pre-clinical tests. The clinical trial protocol — which companies submit to gain approval from review boards — is but an incomplete summary of the IMPD.
The protocol summary failed to report animal deaths during the pre-clinical studies. But Le Figaro revealed that in fact several monkeys died or had to be euthanised during the dose escalation studies. Evidence also emerged showing that two dogs had to be euthanised in the 13-week dog study due to lung lesions – both from the highest dose group. None of these animal deaths were described in the Bial trial protocol. (Wikipedia notes 13, 24, 5)
Below a rough English translation of Le Figaro, “Clinical trial: the document that overwhelms and Biotrial ANSM”
“The internal investigation noted that “the non-clinical evaluator submitted its report (…) alerting the [ANSM] evaluator on a central nervous system neuro-effect” particularly the lesions observed in dogs, mice, rats and monkeys. Alas, this alert did not prevent the ANSM clinical evaluation to conclude that “patient safety is ensured in this study.” Furthermore, the Director of Evaluation notes that “the clinical evaluation report does not include the signals of the non-clinical evaluator of neurological effects observed in animals.” Finally, the clinical report highlights that this is a first-in-man.
Another failure by the official report was the occurrence of adverse effects at lower doses than that which the volunteer who died in hospital had ingested. These side effects included blurred vision, which were identified by the specialized scientific committee (CSST) in early March; but they were disregarded. Thus, two volunteers (cohort MAD) who took 10 mg of the molecule presented blurred vision and diplopia (double vision) on two occasions. Another volunteer (in 2308) couldn’t sleep twice, each time 5:15 after taking the product. Another volunteer (2305) also experienced four episodes of double vision after taking the drug, each time lasting between 1 and 21/2 hours.
But, Le Figaro notes, “this finding was not considered a relevant event by the investigator and the monitoring committee… other adverse reactions at 10 mg. that were ignored were dizziness and exceedingly long-lasting headaches – almost 29 hours at 20 mg. in one subject and 47 hours in another subject.”
Le Figaro reported:
“In total, four different volunteers (in groups that ingested 10 mg and 20) have submitted unusual side effects.” However, the sponsor’s counsel indicated that ‘signs that happen in life [that] are neither widespread nor repeated’ are not worrisome.”
As Dr. Sean Ekins, a respected scientist with 20 years of experience in drug discovery at Big Pharma and start-up companies underscores the bureaucratic nightmare that prevails when the system fails miserably to protect human subjects of research:
“What appears to have been missed in this and the earlier report is that we are still no closer to understanding why the drug resulted in the death of one person and the injury to several others. Its seems, at least from the science side, that we have the same question as in January. All these reports have done is blame both parties rather than get to the bottom of it. This is not science. It is a bureaucratic nightmare.” (Read more at Collaborative Chemistry, a blog by Sean Ekins M.Sc., Ph.D., D.Sc.)
Catherine Hill, a biostatistician who previously served on the ANSM’s scientific advisory board, says that it was “a big mistake” to begin giving the six volunteers the drug on the same day. She says that the trial should have incorporated a delay between volunteers as they started the multiple-dose regimen. “You have to do things reasonably, and I think it’s an unreasonable protocol,” she says.
“A key aspect is a proper interval of time between dosing of successive volunteers,” says biostatistician Sheila Bird of the Medical Research Council Biostatistics Unit at the University of Cambridge, UK, who is a member of the RSS working group, which focuses on ‘first-in-human’ clinical trials.
In an article in the British Journal of Clinical Pharmacology, Professor Michael Eddeleston, a clinical toxicologist at the University of Edinburgh, indicated that both regulators and industry need to rethink preclinical risk assessments:
“Drug pharmacology has to be better described and then studied during the preclinical and clinical studies. This aspect will reduce the risk of similar problems occurring – the starting dose for both TGN1412 and this Bial drug appear to have been far too high.”
“If the available data are comprehensive and accurate, and further investigation does not reveal unreported warning signs, this study has serious implications for ongoing and future review of [first-into-human] FIH clinical trials. All preclinical study documents and clinical data collected during the BIA-102474-101 trial should be made available urgently so that lessons can be learnt.
In the meantime, reviewers and clinical researchers should always ask for information on drug and target interactions and full reports of preclinical toxicity studies, and plan sequential dosing with longer delays between patients and cohorts, particularly if late SAEs might be anticipated. The use of individual patient pharmacokinetic and dynamic data should guide sequential dosing. A process for systematic risk assessment, like that currently used in the Netherlands, should be applied routinely to all trials with novel compounds.
Sheila Bird of Cambridge and the Royal Society of Statisticians stresses the importance of the release of all preclinical information to ensure the safety of participants in other clinical studies. “There are other studies going on around the world right now, and we want to know what the design problems were.” (Nature, January 2016)
Read also about a very similar publicly reported catastrophic experiment conducted in Scotland in 2006. That experiment ended in horrific tragic consequences for the six human subjects who were exposed to a monoclonal antibody, TGN1412, and suffered as a result of the experiment, liver failure. (Read more here, here)
Dr. Jeffrey Drazen, editor in chief of The New England Journal of Medicine, defended this catastrophic experiment – as he has defended other ethically dubious experiments whenever they have been publicly exposed – by invoking “the future health of the world population demands that we not let adverse events put an end to medical progress.” (Volunteers at Risk)
We are not aware that Dr. Drazen or any of the proponents who similarly argue for “the greater good” are lining up to volunteer as human subjects of risky medical experiments.