Drug Ads Should Take A Long View, DDMAC Says In Citing Time-To-Onset Claims

FDA sends notice of violation letters to Dow Pharmaceutical Sciences (Valeant) and Novartis for stretching a point in promotional materials for Acanya Gel and Focalin XR, respectively.

Sponsors should not claim advantages for their products based on clinical trial results from a given point or points in time when the drug in question is supposed to work over a prolonged period, FDA said in two letters citing time-to-action claims in drug ads.

FDA's Division of Drug Marketing, Advertising and Communications made that point in two separate "notice of violation" letters to two different companies for drugs treating different conditions: a May 31 letter to Novartis for a "professional one point leave behind detail aid" for its attention deficit hyperactivity disorder drug Focalin XR (dexmethylphenidate HCl extended-release capsules) and a June 16 letter to Dow Pharmaceutical Sciences for its acne treatment Acanya Gel (clindamycin phosphate and benzoyl peroxide, 1.2%/2.5%).

Two Weeks To Unbelievably Clear Skin

Dow is the NDA holder of record for Acanya, although the company was acquired by Valeant Pharmaceuticals International for $285 million in December 2008, which launched the product the following March (Also see "Deals Of The Week: Exelixis/BMS, Valeant/Dow, Novartis Option Fund/Ascent" - Pink Sheet, 15 Dec, 2008.).

DDMAC cited the company for a website for Acanya, which is indicated for the topical treatment of acne vulgaris in patients age 12 and up. "In clinical studies, some patients using Acanya Gel daily saw improvement as soon as two weeks, which continued throughout a 12-week treatment period," the company claimed on the website, accompanying this with "a graphic depicting a 19-year-old patient's acne continuously improving from baseline through weeks four, eight and 12."

DDMAC said in its letter that this was unacceptable, even though patients in the clinical trials were evaluated at weeks four, eight and 12, because the two earlier time points "were not pre-specified endpoints in the clinical studies. Therefore, the clinical studies for Acanya do not provide substantial evidence or substantial clinical experience to support claims and presentations implying that Acanya works as early as two weeks and throughout a 12-week treatment period."

On top of that, there were large pictures on the Acanya website "of faces (nose to chin) depicting completely clear, acne-free skin," but only 28% and 29% of patients who took the drug in two clinical trials actually achieved skin that was almost or completely free of acne according to a standard scale.

Moreover, DDMAC said, the website omitted material facts about Acanya and minimized risk information about the drug, for example by failing to note that it is contraindicated in patients with a history of Crohn's disease, that severe abdominal cramps are a symptom of colitis that may be caused by the drug, that it may cause serious allergic reactions and that patients who experience them should stop using Acanya and call their doctor right away.

The website also did not present risks in order of severity and implied that Acanya is gentle to the skin, when in the clinical trials up to 10% of patients experienced mild or moderate burning, up to 7% experienced mild or moderate stinging, and symptoms such as mild or moderate erythema, scaling and itching were also common.

The overly aggressive advertising on the patient-directed website, which is the only direct-to-consumer advertising Valeant has engaged in for Acanya, may have had its impact. Sales of the gel nearly doubled from about $12 million in 2009 to $23 million last year.

But Valeant says it has taken the website down in order to remove all advertising and promotional material to address the agency's comments and to make required changes, and that it hopes to have the website back online with the appropriate changes within the next several weeks.

"We are committed to complying with all applicable regulations as they relate to promotional activities and we are working quickly to address and correct the issues raised by the agency," Valeant said in an email. "We are carefully reviewing all materials and have put additional processes in place to ensure we comply with all applicable regulations in future materials."

Novartis Draws DDMAC Attention For Sixth Time

While the NOV letter to Dow appears to be a first for either that company or Valeant, at least since 1997, the NOV letter over Novartis' detail aid for Focalin is the sixth DDMAC citation the company has received since April 2010 (Also see "Novartis Advertising Cited By FDA For Fifth Time In Less Than A Year" - Pink Sheet, 14 Feb, 2011.).

In fact, Novartis has already received another notice-of-violation letter, this one from CBER's advertising branch for its Menveo meningitis vaccine (see (Also see "Menveo Ad Should Not List CDC Recommendations Because It Does Not Meet Them, FDA Says" - Pink Sheet, 6 Jul, 2011.) ).

The company's Focalin promotions landed it in hot water for what DDMAC judged a misleading comparison to Johnson & Johnson's Concerta (methylphenidate) in the detail aid, which Novartis sales representatives provided to health care professionals beginning last year.

As with Dow's Acanya claim, the problem was an attempt to extrapolate from results at a single point of time to a much longer period. Novartis cited two clinical trials that compared Focalin XR with Concerta in ADHD patients two hours after dosing.

This was unacceptable as a promotional point, DDMAC said, because "Treatment for ADHD consists of symptom relief over an extended time period. ...By focusing on the twohour 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 also rejected a less specific promotional claim ("When considering an ADHD medication think Focalin XR first for a fast start.") because it "misleadingly implies that Focalin XR is better or more effective than other ADHD medications, and therefore, should be the 'first' choice when considering treatment options. This superiority claim is not supported by substantial evidence or substantial clinical experience."

"Overall, the FDA is unaware of any adequate and well-controlled head-to-head clinical studies to support claims that Focalin XR is superior to other ADHD medications, including Concerta," the letter adds. "If you have data to support these claims, please submit them to FDA for review."

Novartis said in an email, "We are fully complying with the agency's request and will continue to work with DDMAC to ensure that our promotional materials accurately represent the safety and efficacy of our products," adding that it has taken steps to address the claims to which DDMAC objected in the cited detail aid.

"We also reviewed all other active promotional materials and have addressed these claims in other pieces," the firm said.

Focalin and Focalin XR are among Novartis' top sellers, but the brand seems to be under pressure - the immediate-release version has gone generic. Sales, which the company lists together with its brand of methylphenidate, Ritalin and Ritalin LA, grew a sluggish 3% to $464 million in 2010 ($339 million in the U.S. and $125 million in the rest of the world).

Concerta did worse, but from a much higher starting point, with sales dipping 0.5% to $1.319 billion in 2010 - U.S. sales were off 5.8% at $929 million, while sales in the rest of the world increased 14.7% to $390 million.

-Martin Berman-Gorvine ([email protected])