DDMAC to weigh in on trial design?

The FDA Law Blog has an incredibly interesting entry regarding last week's Untitled Letter from the FDA's Division of Drug Marketing, Advertising, and Communications (DDMAC) to Novartis.

The letter, regarding a detail aid for Novartis's Focalin XR, accuses Novartis of making "unsubstantiated superiority claims" for Focalin XR in comparison to Concerta. What is interesting -- and completely new as far as I can tell -- is that the claims DDMAC are taking exception to are, in fact, primary endpoints of two controlled clinical trials:

Treatment for ADHD consists of symptom relief over an extended time period; thus, ADHD medications must control disease symptoms over the entire treatment course. However, the referenced clinical studies only focused on one specific time point (2 hours post-dose) as the primary efficacy measure in the treatment course of Focalin XR and Concerta. By focusing on the 2 hour post-dose time point, the studies did not account for the different pharmacokinetic profiles and subsequent efficacy profiles associated with Focalin XR and Concerta over the entire treatment course.

So, in essence, DDMAC appears to be taking exception to the trial design, not to Novartis's interpretation of the trial results. This would seem to be a dramatic change in scope.

I am not familiar with the trials in question -- I will post an update with more information shortly. Of special interest to me would be to understand: Were these pivotal trials that played a role in Focalin XR's approval? If so, did the FDA review them in a Special Protocol Assessment (and therefore are two distinct branches of FDA providing divergent opinions on these endpoints)?

Go Green, Recycle your Patients

Euthymics, a small Massachusetts-based biotech, recently announced the start of the TRIADE trial, which they describe as “Phase 2b/3a”. I am guessing that that somewhat-rare designation means they’re hoping that this will count as a pivotal trial, but have not yet had formal agreement from FDA on that topic. Part of this may be due to the trial’s design – per the press release, they’re using a Sequential Parallel Comparison Design (SPCD).

This is an intriguing trial design because it takes one of the benefits of traditional crossover designs – increasing statistical power by “reusing” patients in multiple treatments – while avoiding many of the problems, most notably any concerns about the persistence of treatment effect. This is because only a select but key subset of patients – those who were in the control arm but showed no response – are re-randomized to both arms. This group clearly has no treatment effect to persist, so they make an excellent population to further test with. (It’s important to note that all patients are continued on treatment in order to preserve blinding.)

In essence, we have a placebo run-in phase embedded within a traditional trial. It seems worth asking how this trial design compares against a simpler trial that includes such a run-in – I do not see any information on the website to help answer that.

And that points to the major drawback of the SPCD: it’s patented, and therefore not freely available to study and use. As far as I can tell, the design has not been through an FDA Special Protocol Assessment yet, which would certainly be a critical rite of passage towards greater acceptance. While I can appreciate the inventors’ desire to be rewarded for their creative breakthrough in devising the SPCD (and wish them nothing but good fortune for it), it appears that keeping the design proprietary may slow down efforts to validate and promote its use.