On Tuesday, Bristol-Myers Squibb received approval by the U.S. Food and Drug Administration (FDA) for expedited approval to review its antipsychotic medication, Abilify — already approved in the treatment of bipolar and schizophrenia — for treatment of depression in adults too. Typically such expedited approval is requested when a drug has been on the market for awhile and there is additional research data to support its use and effectiveness in another disorder. Keep in mind, “expedited approval” means little, a difference of only 4 months.
CL Psych decided to look at one of the two placebo-controlled studies the revised supplemental New Drug Application for aripiprazole (Abilify) and depression is based upon.
His first point, that a 3-point difference on the depression measure used, is clinically insignificant is important — there is no difference here from a clinical point of view. It should also be noted that the Montgomery-Asberg Depression Rating Scale (MADRS) is an older, rarely used clinical scale that has no widely-accepted cutoff for a definition of clinical depression (although 30 seems to be what is reasonable, Benazzi (1999)). These researchers found a mean score of 26 on this scale, meaning that, according to some researchers, the people studied wouldn’t even meet the accepted definition of clinical depression.
The MADRS is also a clinician-based scale, meaning the professional rates the patient on the severity of depression. Because this isn’t based upon the patient’s subjective depressive feelings, it is intended to be more objective but is also more susceptible to rater bias.
However, we don’t agree with the concerns about the study design. Of course the researchers already established the group treated with antidepressants aren’t likely to respond to that treatment when continued on them. Nor are they likely to show any greater response on placebos. So if Abilify has no effect on depression, we would likely expect there to be no response by the subjects who are taking Abilify. Objective data (in this case, the MADRS scores) don’t care about “a huge disadvantage,” because that’s a human concept, not a data- or logic-based one. From a standard research design perspective, there’s nothing wrong with the design the researchers employed (although a bit novel).
Keep in mind, the Associated Press story CL Psych quoted simply isn’t very factually accurate. BMS isn’t looking to have Abilify approved as a stand-alone treatment medication for depression, but rather as an adjunctive treatment to antidepressant therapy. This is an important difference and explains why this study may have been designed in the manner it was:
Priority Review status for an application or supplement for a drug product is assigned if a product, if approved, would be a significant improvement, compared to marketed products, including non-drug products/therapies in the treatment, diagnosis or prevention of a disease. The FDA goal for reviewing a drug with Priority Review is six months [Ed. – as opposed to the standard 10 month review].
This sNDA is based on data from two six-week, double-blind, randomized, placebo-controlled, multi-center trials (n=743) evaluating the use of adjunctive Abilify in adult patients with a primary diagnosis of major depressive disorder who had an inadequate response to monotherapy with one or more ADTs.
We’re all for picking apart studies (pharma or no), because there are so many badly designed studies out there to choose from! (Seriously, there could easily be an entire site devoted to picking apart the bad science of so much of what is published today as “research.”) But while this particular study’s measures leave a lot to be desired (and I hope the FDA sees through the weak outcome measures purposely chosen), the design is okay (acceptable, but not ideal).
Not sure where the other study on Medline is, it may have simply not made it into the database yet.
Reference: Benazzi, F. (1999). Severity gradation of the Montgomery Asberg Depression Rating Scale (MADRAS) in outpatients. J Psychiatry Neuroscience, 24(1): 51–52.