Abilify: It's Tricky to Rock the FDA

In the "you're kidding me" category, we have a report from Forbes that Abilify (aripiprazole) is going to be going up for FDA priority review as a depression treatment. I was able to track down exactly one placebo-controlled study using this drug as an antidepressant. Participants who did not show satisfactory response to an antidepressant trial were assigned to receive either Abilify or a placebo in addition to their antidepressant. As you'll see, this was a study worthy of close examination.

Study Results. I read the study results and was underwhelmed. The authors (via their ghostwriter(s) to some unknown extent) reported that the difference between those receiving add-on Abilify vs. add-on placebo was three points on the Montgomery-Asberg Depression Rating Scale (MADRS). For perspective, the MADRS has 10 questions, each rated from zero to six. So suppose three of those ten questions show an improvement of one point each. Whoopee. But keep reading -- it becomes bizarre.

Study Design. Patients were initially assigned to receive an antidepressant plus a placebo for eight weeks. Those who failed to respond to treatment were assigned to Abilify + antidepressant or placebo + antidepressant. Those who responded during the initial 8 weeks were then eliminated from the study. So we've already established that antidepressant + placebo didn't work for these people -- yet they were then assigned to treatment for 6 weeks with the same treatment (!) and compared to those who were assigned antidepressant + Abilify. So the antidepressant + placebo group started at a huge disadvantage because it was already established that they did not respond well to such a treatment regimen. No wonder Abilify came out on top (albeit by a modest margin).

Here's an analogy. A group of 100 students is assigned to be tutored by Tutor A regarding math. The students are all tutored for 8 weeks. The 50 students whose math skills improve are sent on their merry way. That leaves 50 students who did not improve under Tutor A's tutelage. So Tutor B comes along to tutor 25 of these students, while Tutor A sticks with 25 of them. Tutor B's students do somewhat better than Tutor A's students on a math test 6 weeks later. Is Tutor B better than tutor A? Not really a fair comparison between Tutor A and Tutor B, is it?

Ghostwriter Watch: Yep, the study acknowledged "Editorial support for the preparation of this manuscript was provided by Ogilvy Healthworld Medical Education; funding was provided by Bristol-Myers Squibb Co." Of the study authors, all but one were employees of BMS or Otsuka (which is also involved in marketing Abilify).

Unless BMS is hiding data somewhere, this is hardly the stuff breakthrough treatments are made of. Not that the FDA has a history for expecting much in terms of efficacy, but seriously -- can we have a study without a ridiculously biased design before we jump on the Abilify for depression bandwagon?

Oh, the wonders of "evidence based medicine." This one reminds me of the ARISE-RD study for Risperdal as a depression treatment.

Update: I forgot to mention that this is not the first time I've been puzzled by Abilify's claims. For information on how Abilify is supposedly a great long-term treatment for bipolar disorder, you really have to get the story from Furious Seasons, who had a great post on the topic in December 2006. Get ready for more flimsy evidence from BMS.