DDMAC – When Two Well-Controlled Studies Do Not Equal Substantial Evidence

By Dara Katcher Levy –

Last week, FDA’s Division of Drug Marketing, Advertising, and Communications (“DDMAC”) released an Untitled Letter issued to Novartis on May 31st, which alleges the company made unsubstantiated superiority claims in a detail aid for its ADHD drug, Focalin XR.  Unlike most promotional material that trigger DDMAC letters citing unsubstantiated superiority claims, the promotional claims that were the subject of this letter were based on the statistically significant results of the primary endpoints of two comparative studies.  In addition to the sections of the Federal Food, Drug, and Cosmetic Act, DDMAC cites violations of regulations at 21 C.F.R. § 202.1(e)(6)(ii), (xviii); (e)(7)(1) and (ii).

The Focalin XR detail aid contained the following information, cited by DDMAC:

• Two well-controlled studies confirmed the efficacy of Focalin XR versus Concerta at 2 hours postdose.
• Graph titled, “ADJUSTED MEAN CHANGE IN SKAMP-COMBINED SCORE FROM PREDOSE TO 2 HOURS POSTDOSE,” which compares Focalin XR 20 mg and Concerta 36 mg.
• Focalin XR demonstrated statistically significant superior efficacy versus Concerta 2 hours postdose.
• Conclusion – Two well-controlled studies confirmed the superior efficacy of Focalin XR 20 mg versus Concerta 36 mg at 2 hours postdose.

We note that each claim cited by DDMAC contained the phrase, “2 hours postdose.” 

The DDMAC letter alleges that the claims are misleading in that they imply a general superiority of Focalin XR based on the benefit demonstrated at 2 hours.  DDMAC states that “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.”  DDMAC then discusses how each drug is formulated, when each drug’s peak efficacy occurs, and states that the two referenced studies which suggest greater Focalin XR symptom relief at 2 hours also suggest that Concerta may deliver greater symptom relief than Focalin XR from hour nine and beyond.

What is striking is that DDMAC does not take issue with the truthfulness of the statement as written, instead, it focuses on the implication of generalized superiority.  We note the regulatory language in 21 C.F.R. § 202.1(e)(6)(ii) addresses misleading comparative statements that imply greater efficacy “in some particular.”  We would argue that the contextualizing statements of “2 hours postdose” provide that particular.

Further, DDMAC cites to 21 C.F.R. § 202.1(e)(7)(i) and (ii), alleging that the study is inadequate in design, scope, or conduct to furnish significant support for the information, and that the claim has not been demonstrated to have clinical significance or validity.  Presumably, this relates to DDMAC’s allegation that the company failed to analyze the two drugs for a longer period of time (“over the entire treatment course”).  What is interesting, however, is that FDA apparently does give consideration to measures of efficacy at hourly timepoints post dose.  Although not the single pivotal trial, the Focalin XR prescribing information references three additional studies evaluated by reviewers that looked at efficacy in hourly timepoints post dose v. placebo using the same rating scale (SKAMP) as that used in the comparative studies. One study evaluated efficacy 0.5, 1, 3, 4, 5, 7, 9, 10, 11 and 12 hours post dose, and another 1, 2, 4, 6, 8, 9, 10, 11 and 12 hours post dose.  A treatment effect study is also referenced, which evaluated efficacy at .5 hours post dose.  This may undercut DDMAC’s argument that a 2 hour timepoint is not of clinical significance.

We have to wonder whether DDMAC is just picking on Novartis with this one because of its track record.  We’ve witnessed quite a number of comparative promotional pieces currently in the marketplace, supported by a lot less data than a head-to-head study (let alone two!), and these seem to be whizzing under the radar screen over at DDMAC.  Is this more of a general message from DDMAC to industry about the use of comparative promotional claims in general?  We’ll watch and see DDMAC’s continued regulation through enforcement on the issue.