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"Me Too" Drugs

By a Nose in a Head to Head

One of the other incorrect lessons that people might take away from the press accounts of the antipsychotic trial is that drug companies have been comparing their medications to placebo too often. And why would you do that unless you were scared that you wouldn’t be better than the competition? What’s with these people, anyway?
Well, there are fields where placebo-controlled trials take place, and fields where they don’t. It depends on the disease and options available to treat it. Cancer trials, for example, are very rarely run against placebo, unless there’s just nothing left to do. (You’ll see this with drugs that are meant for late-stage patients or those who have failed existing therapies.)
Antipsychotics are generally compared to an existing standard of care, because it’s unethical to leave someone untreated when they’ve already been diagnosed as schizophrenic. The problem that the CATIE trial uncovered, though, is that many trials are run against haloperidol (known as Haldol). That’s a typical older drug, and companies have been showing that they have better efficacy and fewer side effects than it does. (It’s known to have significant problems with tardive dyskinesia, among other things).
But now we know that perphenazine is a better standard among the older drugs, mostly because of fewer side effects. I don’t think that anyone is going to be able to run a haloperidol-controlled trial for a new antipsychotic. Now you’re going to have to beat perphenazine, which will be a higher standard. The newer drugs have been able to get rid of the so-called extrapyramidal side effects, like tardive dyskinesia, but they haven’t been able to increase their efficacy that much. That’s not going to be enough any more – the ante has gone up in the field of schizophrenia therapy.
Now, if you think that your new drug is really going to cream the competition, running a trial against them is a smart move. There’s no better way to persuade people to prescribe your drug than to show that it’s clearly better than what’s out there now. Another time you see head-to-head trials is when a company is making a run at the leader in a given category. The various attempts to out-do Lipitor are good examples, not that any of them have succeeded. But there really wasn’t a clear leader in the antipsychotic area, and thus no real target to try to knock down. I’d bet that the companies involved strongly suspected that their own drugs weren’t head and shoulders above everything else, either. This is the perfect situation for an outside agency like the NIH to do a comparison study, because if you’re waiting for the companies involved to do it, you’re going to have a pretty long wait.

4 comments on “By a Nose in a Head to Head”

  1. Martin says:

    Wasn’t there also an issue that haldol, when used in clinical practice, is usually prescribed along with an anti-parkinsonian agent? My understanding is that many of the Zyprexa trials did not include the anti-parkinsonian allowing Lilly to make the argument that Zyprexa has a superior side effect profile wrt tardive dyskinesia by excluding the combination treatment typically used.

  2. Paul Hardy says:

    No. Antimuscarinics (“antiparkinsonian” drugs) will affect short-term parkinsonian side-effects but not tardive dyskinesia, which is typically a long term effect.
    The trials of newer antipsychotics sometimes allowed antmuscarinic drugs, sometimes not. Often they _are_ allowed because if your investigators see patients with parkinsonian side-effects they guess it’s the older drug they’re getting, so it’s hard to argue that the trial was really double-blind.
    Derek, will a trial against perphenazine be fully credible? Haloperidol was a standard because of widespread use – it was just the most likely typical antipsychotic. I can’t speak for the US of course, but in the UK perphenazine was always a very marginal therapy. In fact it was more commonly seen as the combo with amitriptyline than on its own.

  3. Derek Lowe says:

    Yep, it’s been a while since I worked in the dementia field, but I never thought of perphenazine as any big deal. Apparently no one else did, either, but if this trial is really seen as credible, I’d think that the FDA might ask for it. . .

  4. wally shaykhoun says:

    would like to know why Haldol would not show up in blood stream? my sister was on 200 mg of it and she committed suicid while on it + zyprexa. but the medical examiner didn’t find it in her blood

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