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Formally Undecideable

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.

8 comments on “Formally Undecideable”

  1. Still Scared of Dinosaurs says:

    I tend to think of everything in terms of probabilities, and sometimes this is even useful. As you note, the chances of a drug passing human testing is greater when it has already passed animal tox (twice, at least), and the contrapositive is also true.
    While it may pass human trials after failing, it’s almost never worth finding out because there is always something more promising in the pipeline. (Isn’t there?)
    We have to remember that animal tox, while imperfect, is really pretty good. It’s the animal efficacy models that don’t work well enough, and the drugs that pass tox and fail in the clinic do so because it turns out that there are safe human doses and effective human doses but no overlap between the two. And it is characterising and exploiting the overlap that is in my mind the essence of drug developement.

  2. David says:

    Do you really want to have a hand in bringing the next undertested thalidomide into the clinic?

  3. Milo says:

    I wonder if the use of AMS to do micro dosing PK on humans may help improve the situation. I don’t think you can get an awful lot of tox information from this, but it would allow you to enter humans earlier in the process.
    Is this being done in Pharma now?

  4. LNT says:

    From what I understand, the FDA just issued guidance on microdosing very recently. If companies are doing it, they are in the very early stages and are probably just experimenting with its usefullness.
    I could be wrong, but I think that microdosing will have a significant effect on the way we do late-stage drug discovery. It would be wonderful to microdose our 3 best compounds in humans and pick the “best” compound to go into a phase I trial.

  5. This brings to mind Tegenero’s candidate TGN1412 [subscription req’d], the CD28-mAb agonist that sickened the British volunteers a few months ago. They were really caught off-guard by the human trials, because nothing suspicious ever showed up in the animal experiments (rabbit, monkey, presumably rodent too). They probably thought Phase I would be the least of their concerns.
    As they say, “nothin’s ever that easy.”

  6. secret milkshake says:

    Thalidomide is a pretty useful antiinflammatory and antiangiogenesis drug (if not very clean). It was the marketing – for morning sickness of pregnant women – that did it.
    Some favorite antipsychotics are “broad” = dirty profile but they work even if it is not quite clear why. Nobody could developed them rationaly, by targeting a single protein/receptor.
    Fluconazole has a rather poor activity in vitro – compared to other azoles – and it would have not been found if they used the established assays – fortunately the activity assay used in this case was a low-throughput fungal infection animal test.
    I think we should do phenotypical cell based assay as early in the project as possible and go into animal-based studies with several species.
    Look how vastly different dog breeds are – Would it be unethical to breed a strain of miniature dumb monkeys, to replace rodents? I mean, what is so big deal about monkey testing, apart from the price, pigs are pretty smart and nobody feels much sorry about eating them.

  7. Still Scared of Dinosaurs says:

    Your newfangled monkeys would have to be pretty extra dumb. Too dumb to open their cages, throw poop, or any of the wonderful things I’ve heard monkeys do. But Republicans would still vote for them.

  8. GATC says:

    I knew a primary screening group that would toss things simply for being water insoluble (how did Sustiva ever make it through?). An then there is the other end of the pipeline like GSK who gave away gemifloxacin (Factive) just because of a hand-full of rashes. Tell that to Oscient now……………

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