Friday, January 15, 2016

News alert: Cinical trial disaster Friday January 15, 2016

I just finished reading a news alert from Reuters entitled "French drug trial disaster leaves one brain dead, five injured", written by Matthias Blamont, and dated Fri Jan 15, 2016. Though preliminary, it seems that one person is brain dead and five persons hospitalized after taking part in a first-in-man clinical trial.

A first-in-man trial is the first clinical trial in which humans are exposed to a drug; all previous trials for the drug having been performed in animals. First-in-man trials have special risks because humans many react to drugs in ways that non-humans do not. Such unpredictable reactions are often due to human-specific immune or inflammatory response pathways.

The earliest reports are preliminary, but I assume that additional information will come out over the next days and weeks. I hope that no reports of additional casualties will follow.

In my book Machiavelli's Laboratory, I discussed another first-in-man trial, and I thought you might appreciate reading an excerpt from the discussion, at this time.

Clinical trials are experiments, and unexpected events may occur. Simon LeVay recounts a clinical trial that went terribly wrong (1). The drug, TGN1412 is a monocolonal antibody developed by a biotechnology company. The biotechnology company provided TGN1412 to a drug-testing company, for the purposes of conducting trials in humans. After preliminary safety tests in laboratory animals, a safe dose was selected for humans.

Eight paid healthy volunteers were assembled. These subjects would be the first humans to receive the test drug, under any conditions. In a single session, six of the volunteers were infused with TGN1412, and two volunteers were infused with a placebo. In about an hour, all six of the subjects developed cytokine storm, a life-threatening condition in which an immune-response precipitates shock, and a wide range of extreme system-wide responses, including shock, and multi-organ failure. Prompt treatment saved all their lives. Two of the six had prolonged hospital courses. The incident occurred in 2006, and the six patients must now deal with long-term medical consequences of the event.

When a new drug is administered in humans, for the very first time (a so-called first-in-man trial), you never know what to expect. That being the case, why were all of the subject treated at the same time? Furthermore, why were all of the volunteers given the same dosage of the drug? Wouldn't it make sense to start with a very small dose, carefully observing the patient over a day or more, and then proceeding to a somewhat higher dose on the next patient. Another aspect of the trial that eventually came to light involved the speed of infusion of the drug. Would it not have been prudent to infuse the drug slowly, so that the infusion could have been stopped if there were any measured rapid effects?

An expert panel was assembled, to review the incident and to make recommendations. Among their conclusions, "New agents in first-in-man trials should be administered sequentially to subjects with an appropriate period of observation between dosing of individual subjects. (2)"

1. LeVay S. When Science Goes Wrong. Twelve Tales from the Dark Side of Discovery. Plume, New York, pp 160-180, 2008.

2. Expert scientific group on phase one clinical trials: final report. Her Majesty's Stationery Office November 3O, 2006.

-Jules Berman (copyrighted material)

key words: clinical trial, medical disaster