The recent clinical trial in France which left one dead and five critically ill raises a question: what can be done to increase safety and transparency?
WARNING: Contains images which some may find distressing.
What happened in France?
A recent clinical trial on 90 volunteers in France has just gone horribly wrong: five men displayed adverse reactions and one is dead. The company running the study, Biotrial, had been conducting such trials since 1989. Whilst it is important to emphasise that the vast majority of clinical trials are essential for the development of new medicines and are safely conducted, it does raise an important question; is everything possible being done to ensure that clinical trials are safe and conducted in the context of well-informed background research? No.
Has this occurred before?
A similar incident took place in London in 2006; six volunteers – all men – turned up at Northwick Park Hospital, each being paid £2000 to take part in the trial. The new drug being tested on them was named TGN1412. This was a Phase I trial, otherwise known as a “first-in-man” trial, where the drug is assessed for safety in healthy human subjects, with the dosage being increased slowly over time. The drug had been identified as a potential treatment for rheumatoid arthritis, a form of swelling and inflammation in the bone joints caused by the body being attacked by its own immune system.
The men were given the drug, and an hour later worrying symptoms began. They described having headaches and a general feeling of unease. Then, what doctors described as a “cytokine storm” commenced, a full blown assault by the immune system on the body itself leading to multiple organ failure. One man’s blood pressure fell dramatically; another went into respiratory failure as his lungs filled up with fluid. Their fingers and toes started blackening, shrivelling and falling as necrosis – cell and tissue death – commenced. Another’s head ballooned so much that hospital staff described him as the “elephant man”. All six were ventilated on intensive care, and with the supreme efforts of the medical team, all six just about managed to come out alive. Soon after, the company that developed the drug, TeGenero, was sued and thereafter filed for bankruptcy, unable to pay back compensation. Parallels can indeed be drawn between this incident and the recent one in France ten years later.
So what was done about it?
The Department of Health brought together an “Expert Scientific Group” to investigate what had gone wrong. They came up with two concerns; the first was the administration of a new, unknown drug to six volunteers at once instead of giving it in staggered doses. This received lots of media attention and lessons have now been learnt; in the recent French clinical trial, only five of the 90 volunteers underwent an adverse reaction. Four are now in a more stable condition.
But it was the second issue raised by the group that, sadly, seems largely ignored. They questioned: could the TGN1412 incident ave been prevented? It was a new drug, affecting the immune system in ways that were poorly understood, and had only been tested in animals before. Nonetheless, the group did find that there had been a similar experience previously. TGN1412 is a molecule that targets a type of white blood cell (which make up the body’s defence system) with a “marker” on its surface called CD28. In fact, one researcher had previously carried out a study looking at the effect of another molecule that interacts with CD28, and the symptoms developed by the patient had been extremely similar to those of the six volunteers. The problem, however, was that the researcher had not published these results, so no one ever could have realised that TGN1412 would be harmful, even though the data was there, buried deep in some researcher’s drawer.
And therein lies the big concern of evidence-based medicine. We cannot blame the original researcher for not publishing his results – and thereby having missed the opportunity to save the health of the six men. He was working in an academic environment where positive results were looked up to and negative results in a trial seen as a failure; where publication bias was pervasive; where positive results were two times more likely to be published than negative results.
And this distortion, at the core of this supposedly evidence-based medicine, has not stopped. Negative results are not a failure; they tell you that a medicine does not work, meaning that harm could potentially be prevented and money not wasted on conducting the same trial again. If negative results were published without being shoved into the corner, they would provide necessary information for researchers. This way, volunteers – who are essential for medical research and without whom we would not have the medicines we have today – will not be afraid to partake in trials, further expanding the research base for medical academics and opening up new pathways for trials.
As the investigation into the clinical trial in France is still ongoing, we cannot be certain that earlier trials – albeit unpublished – had been conducted. But tackling publication bias and creating an environment where negative results are just as appreciated as positive results will go a long way in advancing medicine and making clinical trials safer and less wasteful. Otherwise, missing data will continue to kill.