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Commentary

Formally Undecidable
Derek Lowe, In the Pipeline, 6-20-06

Derek Lowe, author of the blog "In the Pipeline", tries to explain why ferreting out "good" (i.e. safe) drugs from dangerous ones remains so difficult. Part of the reason, he thinks, is that animal testing for drug toxicity is an imperfect science while it remains the best proxy for human safety that we have at present. Along the way, he also explains just how hard and complex drug development is, a point that the lay public rarely appreciates.

A comment to the last post asked a good question, one that occurs to everyone in the drug industry early in their career: how many useful drugs do we lose due to falsely alarming toxicity results in animals?

The answer is, naturally, that we don‘t know, and we can‘t. Not in the world as we know it, anyway. The only way to really find out would be to give compounds to humans that have shown major problems in rats and dogs, and that‘s just not going to happen. It‘s unethical, it‘s dangerous, and even if you didn‘t care about such things, the lawyers would find some thing you did care about and go after it.

But how often does this possibility come up? Well, all the time, actually. I don‘t think that the industry‘s failure rates are well appreciated by the general public. The 1990s showed that about one in ten compounds that entered Phase I made it through to the market, which is certainly awful enough. But rats and dogs kill compounds before they even get to Phase I, and the failure rate of initiated projects making it to the clinic at all is much higher.

So it‘s not like we take all these rat-killers on to humans, despite what the lunatic fringe of the pharma-bashers might think. Nope, these are the safe ones that go on to cause all the trouble. "Oh, but are they?" comes the question. "How do you know that your animal results aren‘t full of false green lights, too?" That‘s a worrisome question, but there are a lot of good reasons to think that the things we get rid of are mostly trouble. For all the metabolic and physiological differences between rodents, dogs, and humans, there are even more important similarities. The odds are that most things that will sicken one of those animals are going to land on a homologous pathway in humans. And the more basic and important the pathway is, the greater the chance (for the most part) that the similarities will be still be strong enough to cause an overlap.

But there are exceptions in both directions. We know for a fact that there are compound that are more toxic to various animal species than they are to humans, and vice versa. But we play the odds, because we have no choice. Whenever a compound passes animal tox, we hope that it won‘t be one of the rare ones that‘s worse in humans. But when a compound fails in the animals, there‘s simply no point in wondering if it might be OK if it were taken on. Because it won‘t be.

Lowe‘s underlying point is a very sobering one: the safe drugs do usually make it to market. Getting better at producing safe drugs is not a function of the trial bar, or of making heartless pharma companies "care" about patients. It is, in the first and last place, about better technology.



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