In January, the news emerged that a drug trial had gone horribly wrong. Of the 108 volunteers who participated, six were hospitalised and one died, with three of the men suffering "a handicap that could be irreversible".
The disaster, which occurred in the private laboratory Biotrial in Rennes, France, spelled an unfortunate outcome for the experimental medication BIA 10-2474 that was under development by Bial. Designed to treat anxiety and motor disorders, the drug was intended to act on the body’s endocannaboid system, suppressing a particular enzyme and impacting receptors that regulate pain and mood.
In some respects, it seemed redolent of the Northwick Park trial of 2006, a phase I trial for the drug TGN1412 that left six healthy young men in London fighting for their lives. Manufactured by TeGenero the drug designed for leukemia and chronic inflammatory conditions left the victims feeling like their "brains were on fire" and is thought to have permanently damaged their immune systems.
Back then, serious questions were raised about the study design and the ethical issues at stake, with an expert panel penning a series of recommendations in response to the tragic outcome. Outlined in the Duff report, these recommendations applied to early stage, ‘first-to-human’ trials using new drugs, and aimed to mitigate the risk of such an incident happening again.
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Unfortunately, with history seeming to repeat itself, it is not altogether clear that the necessary hard lessons have been learnt. While it is still too early to determine the issues at stake, or to say where blame should be apportioned, it is clear that the months ahead will involve some uncomfortable investigations.
Regulatory failures
Barrister Christopher Roy-Toole worked on the Newcastle and North Tyneside Number 1 Ethics Committee between 2006 and 2016. Since taking a sabbatical in 2013, he has been submitting evidence to Parliamentary Select Committee enquiries dealing with clinical trial research, and has written a number of private articles re-examining the TGN1412 disaster from a new perspective.
The Rennes disaster, he says, is likely to prompt scrutiny about the failures of the current regulatory system.
"The similarities between the disasters at Rennes and Northwick Park may prove to be more than superficial," he says. "These disasters could point to systemic weaknesses in the European system for drug trial regulation."
Roy-Toole thinks that the current form of regulation is due for an overhaul. Not only are ethics committees under-resourced, with the role being entirely voluntary and unpaid, but they are poorly informed by scientific guidance. He believes they should be fused with the national competent authority (in the UK, the Clinical Trials Unit of the MHRA) to provide a single decision on each clinical trial protocol. This would avoid the pitfalls of a system he dubs "disjointed and unsafe".
"The Clinical Trials Directive of 2001 currently shapes the regulatory system for drug trials across Europe," he says. "It requires an ethics committee and a competent authority to approve every drug trial in every member state, but these bodies are invariably separate to each other – they review the science and the ethics of the research separately. That separation of science from ethics is illogical because the ethics committee cannot decide on risk and benefit in research without considering scientific factors."
In the case of a clinical trial, this means looking at the quality of the scientific design, the method for data gathering, and the safety of any diagnostic or sampling procedures to be used. Unfortunately, the overwhelming majority of ethics committees lack access to a scientific review, leading to poor information flow between the bodies involved.
"It allows for ‘black holes’ to open up in the decision-making process for clinical trial approval," says Roy-Toole. "We cannot have a situation where volunteer ethics committees are expected to ‘muddle by’ alone and without access to expert independent opinion. That is how accidents happen.
The TGN1412 disaster and the Rennes disaster need to be examined in this light."
Ethical errors
There are also questions to be asked about the relationship between laboratory and ethics board. The CPP Ouest VI ethics committee, which examined the protocol for the Rennes trial, had examined 17 of Biotrial’s other protocols in 2015, prompting fears that the two were overly cosy and that mistakes may have been overlooked.
"Did the ethics committee make assumptions about the competence of the protocol or the researchers that were over-optimistic?" asks Roy-Toole. "Professor Adam Hedgecoe has asserted that this was a factor in the occurrence of the TGN1412 disaster. It points to the need to scrap the power of the applicant to choose its own ethics committee. There needs to be more of a central or random allocation."
In the Rennes case, the investigators have stated they will undertake a thorough review of CPP Ouest VI, looking at whether it lacked resources and scientific assistance, whether it was overburdened by increasingly complex protocols;, and whether the voluntary nature of the work may have put people off.
They will also investigate which specific errors were made. For instance, were there too many participants? The trial featured 128 volunteers, of whom 90 received the drug – this number is higher than might be expected for a phase I trial, in which the substance has never been tested on humans.
Similarly, was the dosing regimen unsafe? The Duff report made recommendations that discouraged simultaneous dosing without justification, but the Rennes trial appears to have adopted a simultaneous dosing regimen of a type similar to that used at Northwick Park.
As it transpired, the ill patients all received the same high dose without anyone (a ‘sentinel’) going first. A scientific committee, set up by the French National Agency for Medicines and Health Products Safety, has already reported on the medical consequences. It seems that at the dose administered – around ten to 40 times higher than what was needed to block the target enzyme – the patients sustained damage to their brains, particularly the hippocampus and pons, while the patients on lower doses faced no consistent adverse reactions.
"It was the job of the ethics committee to examine the ethical implications of the design of the study," Roy-Toole says. "Dosing regimens should fall within their remit to consider. So did the ethics committee make an error in this and why?"
Changes afoot
On 24 March, the scientific committee will reconvene to assess what may have gone wrong. They will ask, for instance, whether the patients who became ill shared particular genetic characteristics, or whether the research molecule produced a toxic metabolite. They have also asked Bial to explain some of its practices – such as why it chose to test such high doses in people – and will eventually make recommendations to the French Government.
Incidents of this nature are highly unusual, with the Rennes disaster having been described as the worst of its kind ever to take place in France. In 2013, a representative from the Medicines & Healthcare Products Regulatory Agency (MHRA) told the BBC an incident such as Northwick Park was unlikely to happen again.
"Clinical trials in the UK have an excellent safety record, and they play a vital role in the development of new medicines, providing evidence so that clinicians can make informed prescribing decisions. Safety problems associated with clinical trials are rare and the risk of a repeat of the incident in 2006 concerning the TGN1412 drug is extremely low."
That said, data subsequently released by the MHRA under Freedom of Information legislation shows that 7,187 people suffered adverse reactions to UK clinical trials between 2010 and 2014. While there were a shocking 761 reports of fatal reactions, none of these were provably linked to the test drug. However, there were 493 life-threatening reactions, 197 of which resulted in significant disability or incapacity. Around 90,000-95,000 people take part in clinical trials each year.
It would be disingenuous to compare phase I trials – which take place in healthy young people – with later stage trials involving sick patients. However, there is clearly room for improvement and, from a regulatory standpoint, this was set to be a year of change even before the Rennes disaster occurred. The EU Clinical Trials Regulation 2014, soon to be implemented across Europe, will replace the existing Clinical Trials Directive and allow the current system to be remodeled, theoretically paving the way for ‘integrated regulation’ of the kind Roy-Toole endorses.
Unfortunately, he is concerned that ethics committees could face an existential threat, as speed and efficiency are prioritised above ethical rigour. He hopes that the latest disaster will at least sound warning bells.
"The regulation allows corners to be cut in the regulatory process," he remarks. "The lobbyists for industry and academic research in Europe want maximum research through the pipeline with the minimum fuss and delay by ethics committees, and the likely course is for governments to cut back their powers. TGN1412 and Rennes should be seen as warning signals of this process to come."
