Taking one for the team

I've been holding off saying anything about this drug test in England that landed six people in the hospital with horrific, bizarre symptoms, because I wanted to get more information. C. Corax has tipped me off to this CNN story which actually raises a new question or two rather than answering any.

This appears to have been a trial of a monoclonal antibody ntended to treat auto-immune disorders -- the same general class of chemical as Tysabri, which we have been discussing. (These are based on an important natural immune system mechanism, and are intended to disable specific proteins in a precisely targeted way. The problem is, of course, that even if that works as expected, those very substances (enzymes, or cytokines, or cellular receptors, or whatever) that are being targeted because they are causing problems might also be performing necessary functions, which seems to be the case with Tysabri.)

Anyhow, that's not a central point. This was a phase I clinical trial. That's the standard protocol for exposing human beings to a new, experimental drug for the first time. The purpose is not to find out if it works, but to establish that isn't far more toxic than expected, and to get some information about how it is metabolized and excreted. All drugs are toxic, as are all compounds, for that matter -- it is only a matter of degree. But since drugs are selected to have powerful biological effects, they are generally speaking more toxic than most substances.

So first the drug developers -- usually a private company -- have to feed the compound to animals, probably rats, and establish a safe level. Then a single human volunteer is given a dose 1/100th of the safe level for rats. This person is closely monitored to see if there are any ill effects. Then a second "volunteer" (actually someone who is paid, perhaps a substantial sum) gets a slightly higher dose, and so on through additional volunteers until it is established that doses expected to be therapeutic can be taken without acute safety issues. Usually after the first few, people start to get the dosages in groups.

Now, it should be obvious that Phase I trials can be dangerous. People aren't rats, so we can't really know whether something is safe for humans until we try it. Occasionally, we find out the hard way that it isn't. It may strike you as unethical to conduct a Phase I trial, but somebody has to try it for the first time, whatever it may be. If nobody were allowed to try anything for the first time, we wouldn't have aspirin or pencillin, and for that matter, we wouldn't be able to eat.

So, did this company do something wrong? Maybe. Maybe the dose was too high compared to what had been seen in animal models. Maybe the animal model made no sense at all, if this antibody targets a protein that doesn't even exist in rats. Maybe they didn't do enough animal testing. Maybe the dose was impure and this is a reaction to a contaminant.

The CNN story quotes one prospective subject as saying that he refused to participate because he found the informed consent forms inadequate. That would definitely be an ethical violation. I had thought that this was the first time anyone had received this compound, in which case it would have been a serious violation to give it to six people at once, but the CNN story also quotes an official of the manufacturer, TeGenero, as saying that the drug had not caused problems in previous testing, so evidently this was a later stage. These volunteers were paid quite a large sum -- $3,500 -- and that does raise alarm bells. The ethical theory behind Phase I trials is that people "volunteer" for them out of largely altruistic motives. The money is supposed to compensate them, not entice them. Of course we know that's a fiction.

Finally, if compounds are suspected of being toxic, they are not given to healthy volunteers, but only to people in the late stages of the disease they are intended to treat, who have little to lose. That was not the case here, these were healthy young people who apparently signed up for the money.

The bottom line, after this rambling essay, is that this case may or may not represent a specific act of negligent or unethical behavior, but it doesn't represent a more general sin. Phase I trials, however problematic, are necessary. Every once in a while, something like this will happen, although we don't yet know whether this particular incident was avoidable.